Note: Descriptions are shown in the official language in which they were submitted.
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EMULSIONS AS SOLID DOSAGE FORMS FOR ORAL ADMINISTRATION
FIELD OF THE INVENTION
The present invention relates to the field of emulsion
compositions and to pharmaceutical dosage forms and the
methods of preparing the same.
BACKGROUND OF THE INVENTION
Certain drugs present significant problems in balancing
the desire for a convenient oral dosing format and the
necessary bioavailability. With some drugs, absorption of an
orally administered dose could be as little as 30~, or less.
Such poorly absorbed drugs often display large inter- and
intra-subject variability in bioavailability. See Aungst,
B.J., J. Pharm. Sci., 82:979-987, 1993. Specific examples of
such drugs, having the average bioavailability given in
parentheses, include methyldopa (250) with a range of 8% to
62 0; and nalbuphine (approximately 17 0) with a range of 6% to
40 0 .
The absorption rate of most drugs depends on two factors:
(1) the dissolution of the drug in physiological fluids and
(2) the absorption process itself, i.e., the process by which
a drug in solution enters the cells at the absorption site
and, finally enters the general circulation. Many drugs are
absorbed by passive diffusion, i.e., a spontaneous migration
of drug molecules from a region of high concentration to a
region of low concentration. Other drugs are absorbed by
active transportation which involves the expenditure of energy
by the body. Some drugs are absorbed by the processes of
pynocytosis or endocytosis which involve the engulfing of
solid particles and the incorporation of such particles into
the cellular contents. However, with these few exceptions,
for solid orally administered drugs, absorbed actively or
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passively, dissolution of the drug is the first step in the
absorption process.
To compensate for the poor absorption displayed by many
drugs, a pharmaceutical formulation may utilize or take
advantage of one or more mechanisms to increase the rate and/
or the extent to which the administered drug is absorbed.
While there are a vast number of such mechanisms, they may be
grouped into the following broad categories: (1) techniques
that increase rate of absorption by enhancing the rate or
extent of dissolution; (2) techniques that increase rate of
absorption by facilitating the absorption process that would
have occurred naturally; and (3) techniques that increase rate
of absorption by inducing an absorption mechanism that would
not naturally have occurred or which would have occurred to an
insignificant extent in the absence of any special absorption-
enhancing mechanism. Incorporation of surfactants to increase
the rate of dissolution of a slowly-dissolving drug is an
example of a technique which takes advantage of the first
mechanism, and incorporation of a chemical substance that
opens tight junctions in order to increase the rate of
absorption of a drug that would normally have been absorbed
slowly through the paracellular route is an example of the use
of the second technique. On the other hand, incorporation of
a drug within oil droplets for the purpose of using the
lymphatic system in the absorption of the drug (where this
would not, otherwise, have occurred) is an example of a third
technique using the third mechanism.
Emulsions have also been used for delivering drugs. The
emulsions are generally delivered only in the form of soft or
hard gelatin capsules, or as a liquid dispensed directly into
the patient's mouth. However, gelatin capsule shells contain
water which can migrate into water-in-oil ("w/o") emulsions.
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This can change the relative proportions of the different
phases of the emulsion and/or cause the gelatin shell to
become dry and susceptible to cracking. Alternatively, a w/o
emulsion can lose water to the gelatin shell, again changing
the proportions of the different emulsion phases or causing
the shell to swell and become soft. The latter effect makes
it difficult for a patient or care-giver to handle the
capsule. Moreover, surfactants and co-surfactants within the
emulsions, often used as emulsifying agents, can react with
the capsule shell. Oil-in-water ("o/w") emulsions generally
cannot be incorporated in such capsules because the water in
the external phase will dissolve the capsule shell. In
addition, gelatin capsules which contain liquids present
handling problems to both the patient and the manufacturers.
Capsule leakage is a common problem and sophisticated
detection systems are sometimes employed to monitor such
leakage. Upon physical handling by the patient, the capsule
may also soften or leak. tnlith prolonged storage at
temperatures and humidity levels that are not as closely
controlled as the environment in a pharmaceutical factory, the
capsule may also swell, shrink or leak.
More recently, powdered solution technology has been
proposed as a technique for the delivery of water-insoluble
drugs. See Spireas et al., "Powdered Solution Technology:
Principles and Mechanisms, Pharm. Research, Vol. 9, No. 10
(1992) and Sheth, A. and Jarowski, C.I., "Use Of Powdered
Solutions To Improve The Dissolution Rate Of Polythiazide
Tablets," Drug Development and Industrial Pharmacy, 16(5),
769-777 (1990). The concept of powdered solutions involves
converting drug solutions or liquid drugs into a dry,
nonadherent, free-flowing compressible powder by admixing the
liquid drugs or drug solutions with a selected carrier.
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Although the dosage form is a solid, the drug is held in a
solubilized liquid state, which enhances diffusion directly
into cells. Alternately, it improves the wetting properties
of the drug and, therefore, enhances dissolution.
Unfortunately, the application of powder solution
technology has been
limited. While the technology offers certain promise in
enhancing the drug-delivery performance, in practice, the
resulting admixture powders generally have undesirable
properties, such as poor and erratic flowability and
compressibility. The disclosure of the co-pending commonly
assigned U.S. patent application and the corresponding
international application PCT/US published under Pub. No.
WO is incorporated herein by reference.
SUMMARY OF THE INVENTION
One aspect of the invention provides an emulsion
composition in the form of a free-flowing, compressible
powder, which includes an admixture of a drug-containing
emulsion and a solid particle adsorbent; wherein the emulsion
is adsorbed on the solid particle adsorbent and forms a free-
flowing, compressible powder. The drug-containing emulsion
remains stable in the composition. Preferably, the drug
containing emulsion has a viscosity of between 1 cps and
400,000 cps, preferably between 400 cps and 200,000 cps and
more preferably between 5,000 cps and 150,000 cps. The drug-
containing emulsion may include between 2o and 50~ active drug
ingredient, preferably between 5o and 40o and more preferably
between 10% and 300.
The emulsion compositions according to this aspect of the
present invention do not limit the types of dosage form and
can be administered to a subject in any pharmaceutically
acceptable dosage. For example, the emulsion compositions may
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be administered as dosage forms, such as tablets; granules,
pellets or other multiparticulates; capsules that can contain
the drug in the form of mini-tablets, beads, or a powder;
suppositories; or as a powder of the emulsion composition
itself, either packaged in a multidose container or as
individual doses.
In another aspect, the invention also provides an
emulsion composition in the form of a free-flowing,
compressible powder. The emulsion composition is an admixture
of a drug-containing self-emulsifying drug delivery system and
solid particle adsorbents. The drug-containing self-
emulsifying drug delivery system is a mixture of oil,
emulsifying agent and active drug ingredient and the mixture
is adsorbed onto the solid particle adsorbent when blended
with the adsorbent. Compositions according to this aspect of
the invention can be made into dosage forms similar to those
discussed above.
The emulsion compositions discussed above may be prepared
by adsorbing a drug-containing emulsion onto a particulate
solid material so as to provide the emulsion composition in
the form of a powder. The powder can then be made into other
solid dosage forms by combination with additional excipients
using conventional processing. The dosage form of the
emulsion composition can also be directly packaged and
administered without further processing.
Administration of drugs in the above-mentioned dosage
forms offers significant advantages over the previously
available methods of administration.
In certain preferred embodiments of the present
invention, absorption of the drug is facilitated by the
administration of the drug-containing-emulsion compositions.
Although the present invention is not limited by any theories
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of operation, it is believed that upon the disintegration of a
dosage form which contains the emulsion compositions of the
invention, emulsion droplets are distributed through a large
volume of the gastrointestinal fluids. This prevents the
formation of large agglomerates of individual emulsion
droplets in localized regions. When the droplets come into
contact with the surface tissues of the body cavity, this
widespread distribution aids in the absorption of the drug
over a large surface area.
In another aspect of the invention, emulsion compositions
and dosage forms containing them are used to enhance the
bioavailability of poorly absorbed drugs that are oil soluble.
This is accomplished by administering these drugs as oil-in-
water (olw) emulsions. The oil soluble drug is distributed as
droplets of an oily solution which is then used to make an
emulsion where water is the continuous phase. The emulsion is
adsorbed onto a powder and formulated into a dosage form.
When ingested, oil droplets may be absorbed by the tissue
together with the incorporated drugs. The oil droplets may
also be positioned adjacent to the absorbing surface so that
the drug in such oil droplets can diffuse into the cell
membrane. In addition, due to the fact that there are many
such droplets, as noted above, the surface area of the
absorbing tissues with which the droplets make contact is
large, thus facilitating absorption. Furthermore, since zn
vivo agglomeration is retarded, absorption can be facilitated.
The emulsion compositions of the present invention may be
also used to promote absorption though the M-cells of Peyer's
patches. These M-cells are involved in the absorption of very
small solid particles of the order of 10 micrometers. Since
the individual solid support particles described in this
disclosure only partially release the emulsion droplets
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following administration of the dosage forms to mammals, there
are free emulsion droplets as well as emulsion droplets
attached to solid particles at the absorption site. In a
preferred embodiment, the droplet-solid support complex is
sufficiently small to be absorbed via the M-cells.
The emulsion globules of the emulsion compositions of the
invention may also promote absorption though the lymphatic
system. Such absorption relates especially to the free
(detached) emulsion droplets but may also relate to the
droplets adsorbed and remain adsorbed onto the carrier
support. Drugs absorbed via the lymphatic system pass
directly from this system into the general blood circulation
and hence avoid the first pass effect.
In addition, emulsion compositions in accordance with the
invention may facilitate administration of drugs that are
subject to metabolic breakdown or degradation in the
gastrointestinal tract, such as, for example, peptides,
proteins, oilgonucleotides and other biological molecules.
Such drugs may be protected within, for example, the oil
droplets in o/w emulsions. As used herein, the word
"protection" refers to the protective effect that reduces the
rate and/ or extent of the drug molecule degradation in vivo.
The emulsion components of the present invention make it
difficult for enzymes and other chemical substances to react
with such drug molecules when they are encased in oil and/or
the emulsifying agent(s).
The emulsions of the present invention are administered
in the form of solid particles which may be further formulated
into solid dosage forms. The drug-containing emulsions are
adsorbed onto a solid particulate (i.e., powder). Although
the drug is in a solid form, it is maintained as an emulsion,
or in the case of self-emulsifying drug delivery systems
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("SEDDS"), in a state .readily converted to an emulsion in
vivo. Preferably, these formulations enhance dissolution into
aqueous fluids and/ or absorption into the body. Although the
present invention is not limited by any theories of operation,
it is believed that the SEDDS is adsorbed on the adsorbent
particles in the form of oil globules or form a film. When
these SEDDS-containing adsobent particles are administered and
in contact with the body fluid, they form an emulsion
composition.
SEDDS consists of all components of the emulsion except
the water i.e. it consists of the oil phase, emulsifying
' agents, anti-oxidants, preservatives and other optional
excipients. Upon mixing with the stomach contents, an
emulsion is formed. It can be distinguished from an emulsion
in that it is a one-phase system: it does not have droplets of
one liquid distributed throughout a second liquid. It can be
distinguished from an oil (that may be adsorbed on a solid
support) by the fact that the oil does not contain emulsifying
agents and, in general, will not form an emulsion upon mixing
with the stomach contents.
In addition to enhancing the saturation concentration
(saturation solubility) of the pharmaceutical substance, the
pharmaceutical compositions and solid dosage forms of the
present invention also increase the substance surface area of
the drug-containing emulsion. The adsorbent particles
increase the area available for interaction with gastro-
intestinal fluids and/or with the site of absorption to
thereby promote absorption of the drug.
In a further preferred aspect of the present invention,
an emulsion composition is in a solid dosage form that is
convenient and easy to handle. The solid dosage forms
represent a robust, stable dosage form. Moreover, the solid
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dosage form that is more patient-acceptable and thus provides
potential for better patient compliance. There are many
patients who do not like to take capsules and for whom an
alternate dosage form, such as a tablet, is preferable. In
addition, the present invention provides a form for the oral
administration of peptides which are generally administered by
injection, which is unpleasant for the patient.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an enlarged top plan view of a tablet according
to one embodiment of the invention.
FIG. 2A is a cross-section view of a tablet according to
another embodiment of the invention.
FIG. 2B is a schematic diagram for the preparation of a
soft tablet.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
An emulsion composition according to one embodiment of
the invention is provided in the form of a free-flowing,
compressible powder, comprising: an admixture of a drug-
containing emulsion and a solid particle adsorbent. The
emulsion is adsorbed on the solid particle adsorbent and
preferably forms a free-flowing, compressible powder, wherein
the drug-containing emulsion is stable in the emulsion
composition.
An emulsion, as referenced to herein, is a system of two
immiscible liquid phases. One of the two phases (the internal
phase) is distributed as droplets/globules throughout the
second phase (the external, or continuous phase). As used
herein, emulsions include oil-in-water (o/w) emulsions, in
which a less polar liquid commonly referred to as an oil is in
the internal phase; and water-in-oil (w/o) emulsions, in which
an aqueous or other relatively polar liquid is in the internal
phase. The present invention also includes the use of self-
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emulsifying drug delivery systems (SEDDS) which consist of all
the components of an o/w emulsion (oil, emulsifying agents,
antioxidant, preservative etc.) except water. Generally, an
emulsion composition containing SEDDS can be prepared by
adsorbing SEDDS to adsorbent powder. Upon administration of
the emulsion compositions containing SEDDS, which forms an
emulsion in vivo upon the admixing with the body fluids.
Generally, emulsions can also be classified as fine emulsions
with globule diameters of less than 5 ~m and coarse emulsion
with globule diameters greater than 5 ~Zmm.
The oil phase in the emulsion can be any nontoxic oil,
which includes, but are not limited to mono-, di- and
triglycerides, fatty acids and their esters, ethers and esters
of propylene glycol or other polyols. The fatty acids and
esters (used as such or where they form part of a glyceride)
may be short chain, medium chain or long chain. As used
herein, medium chain represents a hydrocarbon carbon of C8 to
C12 and short chain is a hydrocarbon chain of less than C$ and
long chain means a hydrocarbon chain of more than C1~.
The water phase in the emulsion can be water, aqueous
solutions, alcohols, alcohol solutions, etc.
The oil phase may be of vegetable or animal origin. The
oil phase may also be synthetic or semisynthetic, or
substances which are nontoxic to the subject or oil in the
emulsions. The oils include, but are not limited to, natural
oils, such as cottonseed oil, soybean oil, sunflower oil;
canola oil; CAPTEX~ (various grades Propylene Glycol Esters
such as Propylene Glycol didecanoate; and Glycerol esters such
as Glyceryl tricaprylate/caprate); MIGLYOL~ (Caprylic/ capric
acid triglycerides; or Caprylic/ capric/linoleic acid
triglycerides; or Caprylic/ capric/succinic acid
triglycerides; or Propylene glycol diester of caprylic/ capric
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acid and admixtures with other agents); CAPMUL~ (available in
different grades, e.g. Capmul MCM. It is mainly mono- and di-
esters of glycerol and of propylene glycol, such as glyceryl
monooleate and propylene glycol monocaprilate. Another grade
consists of polyethylene glycol glyceryl monostearate.); and
MYVACET~ (distilled acetylated monoglyceride emulsifiers).
The formation of emulsions also requires emulsifiers or
emulsifying agents. As used herein, any nontoxic emulsifying
agent may be used in the present emulsion. This includes, but
are not limited to, various grades of the following commercial
products: ARLACEL~ (mainly sorbitan esters); TWEEN~'
(polyoxyethylene sorbitan esters); CENTROPHASE~ (fluid
lecithins); CREMOPHOR~ (polyoxyl castor oil derivatives; or
macrogol ethers; or macrogol esters); LABRAFAC~
(caprylic/capric triglyceride); LABRAFIL~ (polyoxyethylated
glycolysed glycerides); LABRASOL~ (mixture of mono-, di- and
triglycerides and mono-and di-fatty esters of polyethylene
glycol. The predominant fatty acids are C8-C1o caprylic/capric
acids); MYVEROL~; and TAGAT~ (polyethyleneglycol hydrogenated
castor oil; or polyethyleneglycol glyceryl esters); lecithin;
cholesterol and proteins such as casein. Multiple emulsifying
agents can be used to maintain the internal phase distributed
as globules throughout the external phase and to retard
coalescence of the globules into larger drops. In this way,
the two phases can be kept in relative stability for a longer
period of time.
In pharmaceutical emulsions used in the present
invention, one or both phases is a drug or a solution of one
or more drugs. Indeed, either or both the water and the oil
phases may contain drugs at the same time and those drugs may
be the same or different. Any two immiscible liquids that are
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non-toxic and compatible with the part of the mammalian body
to which they are to be applied, may be used.
In the present invention, oil phase, aqueous phase and
emulsifier can be used in a wide range of ratios to make the
emulsions. Oil-in-water emulsions generally contain at least
25% of water by weight, preferably between 60% and 98% and
more preferably between 70% and 90%. The oil phase in the o/w
emulsions is desirably at least 1% of the emulsion by weight,
preferably between 5% and 69% and more preferably between 8%
and 40%. (The active drug ingredient is included in the weight
of the oil phase.) The emulsifier in the emulsions is at
least 0 . 5 % by weight, preferably between 2 % and 25 % and more
preferably between 5 and 10%.
Water-in-oil emulsions generally contain at least 25% oil
phase by weight of the w/o emulsion, preferably between 40%
and 98% and more preferably between 50% and 95%. The water
phase in w/o emulsions desirably is at least 1% of the w/o
emulsion by weight, preferably between 2% and 55% and more
preferably between 5% and 30%. (The active drug ingredient is
included in the weight of the water phase.) The emulsifier
in w/o emulsion desirably is at least 0.5% of the w/o emulsion
by weight, preferably between 2% and 20%, and more preferably
between 4 and 10%.
Emulsifying agents or combinations of agents are used for
o/w or w/o formulations in accordance with the HLB
(hydrophile-lipophile balance) system. w/o emulsions require
low HLB emulsifying agents (HLB value approximately 1 to 7)
and o/w systems require higher HLB emulsifying agents (HLB
value approximately 11 to 18). In general, the type of
emulsifying agent used and the relative proportions of oil and
water determine whether the emulsion is a w/o or o/w emulsion.
This refers to the emulsion upon formation. Some emulsions
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may invert when added to a large volume of the internal phase.
Thus, an emulsion that is prepared as w/o emulsion, upon
consumption by the patient may invert to an o/w emulsion in
the patient's stomach.
Generally, an emulsion can be prepared by mixing the oil
phase, the water phase, the emulsifier, etc in a propeller
mixer, a turbine mixer or other high shear mixer and stirring
the mixtures vigorously.
he adsorbent is placed in the bowl of a suitable mixer,
such as a planetary mixer, and the emulsion is added slowly
with mixing. The rate of addition should not be so fast as to
form clumps of wet material or, alternately, areas that are
much more wet than other areas of powder. If powder clumps or
wet portions of power are encountered, the rate of emulsion
addition should be reduced or, preferably, temporarily stopped
until the wet portion of powder is well distributed throughout
the bulk of the powder. The planetary mixer is well suited to
this operation since it is equipped with a scraper bar that
scrapes material off the sidewalls of the vessel. Overly wet
material often accumulates on the sidewalls and would not have
mixed well with the bulk powder, except for the action of the
scraper bar.
The practice of this invention is, obviously, not limited
to the planetary mixer but any mixer that affords uniform
mixing of powders with liquids will suffice. Mixers that have
dead space should be avoided. A dead space, for purposes of
the present discussion, is one in which powder can collect but
in which space the powder is not subj ect to the mixing action
of the apparatus. Mixers which have a secondary mixing
action, in addition to the primary action, are preferred. The
secondary mixer action may be a scraper (as in the planetary
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mixer) or an intensifier bar or other high shear component.
Generally, the mixing action of the mixer should provide an
intense mixing zone where high shear of the powder is
experienced as well as an additional mixing action which moves
all portions of the powder through the intense mixing zone
i.e. there should be a three dimensional shuffling of the bulk
powder.
The addition of the emulsion to the powder may be
accomplished by the operator simply pouring the emulsion into
the mixer bowl (containing the powder) from a beaker or
measuring cylinder, or by more sophisticated means such as
spraying the liquid onto the powder at a controlled rate. A
peristaltic pump may be used to add liquid at a controlled
rate. The spray nozzle used in conjunction with the
peristaltic pump should, preferably, provide a fine spray. A
spray head that is used with a fluidized bed coater is ideal.
The spray rate should not be so fast, or the droplets so fine,
that there is a large amount of spray that does not reach the
powder but is dissipated outside the mixing bowl. Such over
spray will not be incorporated into the product and this loss
should be minimized.
The present invention is applicable to both water-soluble
and water-insoluble drugs. The drug may be combined with
either the oil phase or the water phase depending on its
solubility and other characteristics. A drug dissolved in one
phase may partition into the other phase to some extent and
that this would affect the bioavailability of the drug, in
general.
Any active substance (drug) may be used in the emulsion.
Liquid drugs, drug solutions, small molecule drugs and
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nutritional supplements, such as vitamins and minerals, are
suitable for use in the present invention.
As used herein, the phrase "small molecule" includes any
inorganic chemical molecules, organic chemical molecules
having a molecular weight of less than 3,000 daltons.
Preferably, the drug is chosen from one or more of the
following categories/groups: abortifacient/interceptive, ace-
inhibitor, cc-adrenergic agonist, (3-adrenergic agonist, o
adrenergic blocker, j3-adrenergic blocker, adrenocortical
steroid, adrenocortical suppressant, adrenocorticotropic
hormone, alcohol deterrent, aldose reductase inhibitor,
aldosterone antagonist, 5-alpha reductase inhibitor, anabolic,
analeptic, analgesic, androgen, angiotensin converting enzyme
inhibitor, angiotensin II receptor antagonist, anorexic,
antacid, anthelmintic, antiacne, antiallergic, antialopecia
agent, antiamebic, antiandrogen, antianginal, antiarrhythmic,
antiarteriosclerotic, antiarthritic/antirheumatic,
antiasthmatic, antibacterial, antibacterial adjuncts,
antibiotic, anticancer, anticholelithogenic,
anticholesteremic, anticholinergic, anticoagulant,
anticonvulsant, antidepressant, antidiabetic, antidiarrheal,
antidiuretic, antidote, antidyskinetic, antieczematic,
antiemetic, antiepileptic, antiestrogen, antifibrotic,
antiflatulent, antifungal, antiglaucoma, antigonadotropin,
antigout, antihemorrhagic, antihistaminic,
antihypercholesterolemic, antihyperlipidemic,
antihyperlipoproteinemic, antihyperphosphatemic,
antihypertensive, antihyperthyroid, antihypotensive,
antihypothyroid, anti-infective, anti-inflammatory,
antileprotic, antileukemic, antilipemic, antimalarial,
antimanic, antimethemoglobinemic, antimigraine, antimycotic,
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antinauseant, antineoplastic, antineoplastic adjunct,
antineutropenic, antiosteoporotic, antipagetic,
antiparkinsonian, antiperistaltic, antipheochromocytoma,
antipneumocystis, antiprostatic hypertrophy, antiprotozoal,
antipruritic, antipsoriatic, antipsychotic, antipyretic,
antirheumatic, antirickettsial, antiseborrheic,
antiseptic/disinfectant, antispasmodic, antisyphilitic,
antithrombocythemic, antithrombotic, antitubercular,
antitumor, antitussive, antiulcerative, antiurolithic,
antivenin, antivertigo, antiviral, an~ciolytic, aromatase
inhibitors, astringent, benzodiazepine antagonist, beta-
blocker, bone resorption inhibitor, bradycardic agent,
bradykinin antagonist, bronchodilator, calcium channel
blocker, calcium regulator, calcium supplement, cancer
chemotherapy, capillary protectant, carbonic anhydrase
inhibitor, cardiac depressant, cardiotonic, cathartic, CCK
antagonist, central stimulant, cerebral vasodilator, chelating
agent, cholecystokinin antagonist, cholelitholytic agent,
choleretic, cholinergic, cholinesterase inhibitor,
cholinesterase reactivator, CNS stimulant, cognition
activator, contraceptive, control of intraocular pressure,
converting enzyme inhibitor, coronary vasodilator,
cytoprotectant, debriding agent, decongestant, depigmentor,
dermatitis herpetiformis suppressant, diagnostic aid,
digestive aid, diuretic, dopamine receptor agonist, dopamine
receptor antagonist, ectoparasiticide, emetic, enkephalinase
inhibitor, enzyme, enzyme cofactor, enzyme inducer, estrogen,
estrogen antagonist, expectorant, fibrinogen receptor
antagonist, gastric and pancreatic secretion stimulant,
gastric proton pump inhibitor, gastric secretion inhibitor,
gastroprokinetic, glucocorticoid, cx-glucosidase inhibitor,
gonad-stimulating principle, gout suppressant, growth hormone
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inhibitor, growth hormone releasing factor, growth stimulant,
hematinic, hematopoietic, hemolytic, hemostatic, heparin
antagonist, hepatoprotectant, histamine H1-receptor antagonist,
histamine H~-receptor antagonist, HIV proteinase inhibitor, HMG
CoA reductase inhibitor, hypnotic, hypocholesteremic,
hypolipidemic, hopotensive, immunomodulator,
immunosuppressant, intropic agent, insulin sensitizer, ion
exchange resin, keratolytic, lactation stimulating hormone,
laxative/cathartic, leukotriene antagonist, LH-RH agonist,
lipotropic, 5-lipoxygenase inhibitor, lupus erythematosus
suppressant, major tranquilizer, matrix metalloproteinase
inhibitor, mineralocorticoid, minor tranquilizer, miotic,
monoamine oxidase inhibitor, mucolytic, muscle relaxant,
mydriatic, narcotic analgesic, narcotic antagonist, nasal
decongestant, neuroleptic, neuromuscular blocking agent,
neuroprotective, nootropic, nsaid, opioid analgesic, oral
contraceptive, ovarian hormone, oxytocic, parasympathomimetic,
pediculicide, pepsin inhibitor, peripheral vasodilator,
peristaltic stimulant, pigmentation agent, plasma volume
expander, potassium channel activator/opener, pressor agent,
progestogen, prolactin inhibitor, prostaglandin/prostaglandin
analog, protease inhibitor, proton pump inhibitor, pulmonary
surfactant, 5cc-reductase inhibitor, replenishers/supplements,
respiratory stimulant, retroviral protease inhibitor, reverse
transcriptase inhibitor, scabicide, sclerosing agent,
sedative/hypnotic, serenic, serotonin noradrenaline reuptake
inhibitor, serotonin receptor agonist, seratonin receptor
antagonist, serotonin uptake inhibitor, skeletal muscle
relaxant, somatostatin analog, spasmolytic, stool softener,
succinylcholine synergist, sympathomimetic, thrombolytic,
thromboxane AZ-receptor antagonist, thromboxane AZ-sythetase
inhibitor, thyroid hormone, thyroid inhibitor, thyrotropic
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hormone, tocolytic, topical protectant, topoisomerase I
inhibitor, topoisomerase II inhibitor, tranquilizer,
ultraviolet screen, uricosuric, vasodilator, vasopressor,
vasoprotectant, vitamin/vitamin source, vulnerary, Wilson's
disease treatment, xanthine oxidase inhibitor.
More preferably, the drug is selected from the group
consisting of acyclovir; auranofin; bretylium; cytarabine;
doxepin; doxorubicin; hydralazine; ketamine; labetalol;
mercaptopurine; methyldopa; nalbuphine; nalozone; pentoxifyll;
pyridostigmine; terbutaline; verapamil; buserelin; calcitonin;
cyclosporin; oxytocin and heparin.
Generally, the drug-containing emulsion contains between
0.5o and 60o active drug ingredient. The active drug
ingredient is preferably in the range of between 2o and 500 of
the total weight of the drug-containing emulsion (both
phases), more preferably between 5o and 40% and the most
preferably between 10o and 300. The drug containing emulsion
preferably has a viscosity of between 1 cps and 400,000 cps,
preferably between 400 cps and 200,000 cps and more preferably
between 5,000 cps and 150,000 cps.
The emulsions are also suitable for the administration of
active substances that display poor bioavailability, slow
absorption or long t~"ax. These include drugs that are poorly
absorbed, drugs that are degraded during passage through the
gastro-intestinal system, such as, for example, proteins,
peptides and other biological molecules. In particular, the
protection offered to a drug contained within the internal oil
phase of an emulsion makes this system particularly suitable
for proteins and peptides and other biological molecules.
As used herein, the phrase "biological molecule" includes, but
is not limited to polypeptides, DNA molecules, RNA molecules,
polysaccharides, etc.
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The emulsion may also contain additional excipients such
as preservatives, antioxidants, colors, flavors and fragrants,
etc. Non-limiting examples of preservatives include
methylparaben, propylparaben, benzoic acid and cetylpyridinium
chloride.
Emulsions, including drug-containing emulsions, have
different characteristics as compared with, for example,
microemulsions. Generally, both emulsions and microemulsions
consist of globules of one phase, e.g. water, in. another
phase, e.g. oil, wherein the emulsion globules have larger
diameter than the microemulsion globules. Generally,
emulsions have globules with mean diameters (the average
diameter of all globules in the emulsion) larger than 0.1 ~m
or 100nm, particularly in the range of 0.16 ~m to 40 Vim, while
microemulsions contain globules having diameter of less than
0.1 Vim. However, emulsions and microemulsions are not
necessarily differentiated by the globule size of the internal
phase. Instead, they may differ in one or more of the
following defining properties:
(a) microemulsions can form easily with little
mixing energy needed and often without heating. They
often form spontaneously, i.e. the ingredients in
the correct proportions spontaneously form
microemulsion once placed in a container. On the
other hand, emulsions are thermodynamically unstable
and require vigorous stirring with a high-shear
mixer and usually need heating to a higher
temperature, e.g. 75°C.
(b) The physical appearances of microemulsion and
emulsion are different. Microemulsions are
transparent like water because the globules in
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microemulsions are too small to refract light.
Emulsions are usually white or cream in color.
(c) Micremulsions are thermodynamically stable at
room temperature. Once the microemulsion is formed,
it can be stable for many years in a sealed
container and under normal storage condition.
Emulsions have a tendency for the individual
globules of the interior phase to coalesce (grow
together) into larger and larger drops over time.
Therefore, emulsion are generally stable for a
relatively shorter period of time in bulk solution
if it is left undisturbed, as the emulsion breaks or
cracks to form completely separate phase, when
compared to an otherwise identical microemulsion.
~ S. Indiran Pather et al., J. Pharm. & Biomed. Anal.
13 (1995) 1283-1289. It is believed that when an
emulsion was adsorbed onto an adsorbent, it remains
stable for a longer period of time than the same
emulsion in bulk solution. Without being limited by
any theory of operation, it is believed that upon
adsorption, dispension of the emulsion on the
adsorbent retards coalescence of the interior phase
globules with one another.
(d) The addition of specific proportions of each of
the components and even their order of mixing plays
a role in the formation of emulsions, which also
differentiates emulsions from microemulsions. Such
knowledge and information on the formation of
emulsions is usually known by those skilled in the
art and may be gleaned from standard pharmaceutical
texts such as Physical Pharmacy by Alfred Martin,
Lea and Febiger, 4th Ed. (1993).
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In a preferred embodiment of the invention, the drug-
containing emulsion comprises emulsion globules having mean or
modal diameters of greater than 100nm, preferably between
120nm and 70 Vim, and more preferably between 160 nm and 10 Vim.
The drug containing emulsion of the emulsion composition is
preferably stable for at least one year when left in a closed
container at 25~C and can be an oil-in-water emulsion, a
water-in-oil emulsion, or a self-emulsifying drug delivery
system, which converts to an emulsion in vitro.
In the present invention, the drug-containing emulsions
are adsorbed/ absorbed onto adsorbents/absorbents (these two
terms are collectively referred to as "adsorbent" or
"adsorbents"). Adsorbents should be nontoxic and should
include fine particles having diameters in the range of 25 nm
to 50 ~Zm, preferably in the range of 50 nm to 30 dam and more
preferably in the range of 100 nm to 20 um. Suitable
adsorbents include, but are not limited to, clays such as
kaolin, bentonite, hectorite and colloidal magnesium aluminum
silicate; silicon dioxide (CAB-0-SIL~ or AEROSIL~); magnesium
trisilicate; aluminum hydroxide; magnesium hydroxide,
magnesium oxide or talc. More preferably the adsorbent is
silicon dioxide.
A further aspect of the invention also provides an
emulsion composition in the form of a free-flowing,
compressible powder, comprising: an admixture of a drug
containing self-emulsifying drug delivery system and a solid
particle adsorbent; preferably, the drug-containing self-
emulsifying drug delivery system is adsorbed onto said solid
particle adsorbent and forms a free-flowing, compressible
powder. Direct compression tableting excipients can also be
added to the free-flowing compressible powder to improve its
compressibility.
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The proportion of emulsion to solid support preferably
varies from about 1:20 to about 10:1. More preferably, the
proportion of emulsion to solid support is about 1:5 to about
2:1.
The drug-containing emulsion composition is prepared by
adsorbing the drug-containing emulsion onto an adsorbent.
Generally, the adsorbent is placed in a mixer and then the
drug-containing emulsion having a predetermined ratio to the
adsorbent, is poured into the mixer at constant stirring to
achieve uniform adsorption of the emulsion to the adsorbent.
The resulting product of adsorbing drug-containing
emulsions to adsorbents should preferably be a free-flowing,
compressible powder. Once the emulsion is adsorbed onto the
solid support, ideally, the powder should resemble a
completely dry powder (as far as observation with the eye can
discern) and the powder is preferably free flowing as defined
in the angle of repose test described below. This is more
easily achieved with an o/w emulsion, partly due to the fact
that the water in the external phase partially evaporates
during the incorporation process. There is an equilibrium
amount of water that is retained on the particles of the solid
support. When adsorbing a w/o emulsion, there is a greater
tendency for the powder to appear slightly "wet".
Nevertheless, even with a w/o emulsion the powder should not
be cohesive. The proportion of emulsion to solid support is
an important factor in determining the extent to which the
powder remains free flowing and dry. However, with the
proportions of solid support to emulsion referred to earlier,
it is possible to obtain a noncohesive mixture. For the
manufacture of compressed tablets, this mixture is then
combined with the other tableting components to obtain a
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compressible blend. This compressible blend should be free
flowing.
The extent to which the powder blend is free flowing is
estimated by conducting an angle of repose test as detailed in
a standard pharmaceutical text such as "The Theory And
Practice Of Industrial Pharmacy" by Lachman, Lieberman and
Kanig (Lea and Febiger, publishers), hereby incorporated by
reference herein. The static angle of repose test is
preferred. When such a test is performed, the final powder
blend should have, preferably, an angle of repose less than 42
degrees, and preferably less than 40 degrees.
In order for the mixture of adsorbent and emulsion to
form a free-flowing powder that can easily be compressed, the
proportion of emulsion is kept relatively low in the emulsion-
adsorbent composition. Consequently, the drug-load in the
drug-containing emulsion becomes a significant factor in
formulating a stable, high bioavailable and high drug-load
composition.
Surprisingly it has been discovered that one can
incorporate a wide range of drug load into such free flowing,
compressible powders while increasing the stability of the
pharmaceutical emulsion, as the emulsions of the present
invention can be formed from a wide range of weight ratios of
water, oil and the emulsifying agent and can be adsorbed onto
a solid particulate adsorbent to form a free flowing,
compressible powder. The final drug dosage form can contain
between 0.1 mg and 1,OOOmg of active drug ingredient/tablet
(of e.g. 2.4 grams), preferably between 5mg and 500mg, more
preferably between 10 mg and 200 mg and the most preferably
between 15 mg and 100 mg.
Coating can also be applied to the individual particles
of the emulsion composition powder; to agglomerates, granules
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or other larger particles incorporating multiple particles of
the composition or to solid dosage forms or portions of dosage
forms. The term "multiparticulate" as used herein means a
composition in the form of multiple particles. Each particle
may be an individual particle of the powder composition or may
be an agglomerate, granule, or other larger particle
incorporating or formed from multiple particles of the powder
composition. The coating can also be used in conjunction with
an effervescence to cause the effervescence to occur at
specific areas of the gastrointestinal tract. Nonlimiting
examples of coatings used in the present invention include:
cellulose derivatives including cellulose acetate phthalate
(CAP); shellac and certain materials sold under the trademark
EUDRAGIT~ (various grades are available with differing
properties and may be used in specific combinations).
Hydroxypropylmethyl cellulose phthallate in a grade that
dissolves at pH 5 is the preferred coating material for
enteric coating purposes, for example when the coating must
resist the acidic environment of the stomach but must dissolve
in the duodenum.
Coatings may preferably be done in a fluidized bed coater
or a coating pan. While either type may be used for both
tablets, powders and multiparticulates, the fluidized bed
coater is preferred for multiparticulates while the pan coater
is preferred for tablets. In the fluidized bed coater
process, the multiparticulates are first prewarmed within the
apparatus by blowing warmed air through the container. If the
active drug ingredient is a temperature-sensitive material,
such as peptide, low temperatures are used so that the potency
of the drug is not affected. The volume of fluidizing air
penetrating the bed per hour is chosen such that the material
to be coated is fluidized and flowing in a gentle pattern.
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The effect of the atomizing air should, additionally, be taken
into account. The coating solution is sprayed on at a rate
that will wet the material to be coated within the spray zone,
have time to flow around the particulates and then be dried
within the drying zone of the apparatus. If the liquid spray
rate is too slow (or the temperature of the drying inlet air
is too high, or the inlet air is too rapid), the liquid
droplets dry before they touch the particles, resulting in the
addition of spray dried material to the multiparticulates.
When the spray rate is too fast (or the inlet air is
introduced too slowly, or its temperature is too low) the
liquid does not dry fast enough. The material remains wet,
causing agglomeration of the material. At the correct
conditions, the coating material neither dries too quickly nor
allows prolonged wetting of the material to be coated. These
operating conditions can be adequately chosen by one
ordinarily skilled in the art.
This invention further provides a solid dosage form for
the administration of a therapeutically effective amount of a
drug, comprising: (1) an emulsion composition in the form of a
free-flowing, compressible powder which comprises an admixture
of a drug-containing emulsion and a solid particle adsorbent;
wherein the emulsion is adsorbed on the solid particle
adsorbent, and (2) optionally excipients, including fillers,
binders, disintegrants, viscosity modifiers, lubricants,
colors, flavors and the like.
In one embodiment of the invention, the solid dosage form
is a tablet, a pellet, a minitablet, or a capsule for oral
administration, or a tablet for intra-oral administration, or
a tablet for vaginal administration, a suppository for vaginal
administration, a suppository for rectal administration. A
tablet for oral administration may be of the type which is
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adapted to release constituents of the tablet within the
mouth, so that the released constituents can be swallowed with
or without the consumption of water or other liquid to assist
swallowing. Powders can also be dosage forms in and of
themselves. The solid dosage form can further comprise a
bioadhesive.
In another embodiment of the invention, the solid dosage
form further comprises an enteric coating maintained over the
dosage form or over the portion of the dosage form which
includes the emulsion composition. The enteric coating
prevents the release of the drug-containing emulsion until a
time at which the dosage form reaches a target area following
oral administration. Any coating that can accomplish this is
contemplated. However, the enteric coating preferably may be
selected from materials of the group consisting of EUDRAGIT
5100 (a methacrylic acid copolymer produced by Rohm Pharma
Gmbh of Germany), sugar, gelatin, hydroxypropyl cellulose or
hydroxypropylmethyl cellulose phthalate, cellulose acetate
phthalate, polyvinylacetate phthalate, methacrylic acid
copolymer, shellac, hydroxypropylmethylcellulose succinate,
cellulose acetate trimellitate, and their mixtures thereof.
In a further embodiment of the invention, the dosage
forms contain materials that aid in releasing the drug in a
specific section of the gastrointestinal tract to promote
site-specific delivery. The chosen site for drug release is
usually the most efficiently absorbing part of the
gastrointestinal tract for the drug in question, or one that
offers some other therapeutic advantage. The added materials
promote site-specific delivery by various mechanisms and this
invention is not limited to any one such mechanism. For
example, the material may be metabolized by enzymes present in
a specific part of the gastrointestinal tract, thus releasing
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the drug in that section. The materials used to promote site-
specific absorption may be used as coatings and/or matrix
materials and include, for example, sugars, polysaccharides,
starches, polymers, and the like.
The solid dosage form can further comprise excipients,
such as, at least one effervescent agent and/or at least one
disintegration agent; wherein the disintegration agent causes
rapid dispersion and breaking up of the dosage form following
oral administration. A pH adjusting substance may also be
used as an excipient.
This invention also provides a method for preparing an
emulsion composition, comprising the steps of: preparing a
drug-containing emulsion and converting the drug-containing
emulsion into a free-flowing, compressible powder by admixing
the drug-containing emulsion with a solid particle adsorbent.
Stable emulsions compositions prepared by the method are also
contemplated.
This invention also provides a method for preparing a
solid dosage form for the vaginal or rectal administration of
a therapeutically effective amount of a drug, comprising the
steps of: preparing a drug-containing emulsion; admixing said
drug-containing emulsion with a solid particle adsorbent to
form a free-flowing compressible powder; incorporating said
free-flowing, compressible powder, with the optional addition
of one or more excipients into a tablet, suppository or other
solid dosage form.
Various ingredients and/or techniques can be used in
combination with the dosage forms of the present invention to
further enhance bioavailability, including, the administration
of agents which aid in the site specific delivery of the drug-
containing emulsions, agents which increase the rate of
dissolution. This may be achieved through the structural and
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fluidity changes to the biological membranes induced by the
chosen surfactants. The selected enhancement technique is
preferably related to the route of drug absorption, i.e.,
paracellular or transcellular. These techniques include, but
are not limited to, the use of additional chemical penetration
enhancers; mucoadhesive materials; effervescent couples; ion
pairing or complexation agents; and the use of lipid and/or
surfactant drug carriers.
A bioadhesive polymer may be included in the dosage form
to increase the contact time between the dosage form and the
mucosa of the most efficiently
adsorbing section of the gastrointestinal tract. See Jonathan
D. Eichman,
"Mechanastic Studies On. Effervescent-Induced Permeability
Enhancement,"
University of Wisconsin-Madison (1997), hereby incorporated by
reference
herein. Nonlimiting examples of known bioadhesives used in
the present
invention include: Carbopol (various grades), sodium carboxy
methylce11u1ose, methylcellulose, polycarbophil (Noveon AA-1),
hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium
alginate, and sodium hyaluronate.
Disintegration agents may also be employed to aid in
dispersion of the drug in the gastrointestinal tract.
Disintegration agents include any pharmaceutically acceptable
effervescent agent. In addition to the effervescence
producing disintegration agents, a dosage form according to
the present invention may include suitable ,noneffervescent
disintegration agents. Nonlimiting examples of disintegration
agents include: microcrystalline cellulose, croscarmelose
sodium, crospovidone, starches and modified starches.
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Apart from the effervescent material within the tablet,
some additional effervescent components or, alternatively,
only sodium bicarbonate (or other
a1k'aline substance) may be present in the coating around the
dosage form.
The purpose of the latter effervescent/alkaline material is to
react within the stomach contents and promote faster stomach
emptying.
Additionally, pH-adjusting substances, as described in
U.S. Patent Application Nos. 09/302,105 and 09/327,814, hereby
incorporated by reference herein, may also be used to increase
absorption of a drug. The various components may be present
in layers within the dosage form or specialized shapes and
geometric arrangements may be employed. Dosage forms
according to the invention can include drugs in addition to
those carried in the emulsion-containing composition.
A tablet in accordance with one embodiment of the present
invention (Fig. 1) includes a core 20, a barrier coating 22
which is, in turn, covered by an effervescent layer 24. An
enteric coating 26 covers the effervescent layer 24. Core 20
includes an emulsion composition of the present invention.
When the tablet reaches the small intestine, the enteric coat
26 dissolves, exposing the effervescent layer. Reaction of
this layer with the aqueous fluid of the gastrointestinal
tract releases carbon dioxide. This aids absorption in
several ways including, for example, the thinning of the mucus
layer, thus bringing the tablet into closer contact with the
absorptive surface (mucosa). Barrier coating 22 prevents the
water within the adsorbed emulsion from reacting with the
effervescent material 24. With some w/o adsorbed emulsions,
it may be possible to omit the barrier coating without causing
extensive deterioration of the tablet. This is due to the
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fact that the effervescent material is protected from the
water of the adsorbed emulsion by the fact that the tiny water
droplets of the emulsion are completely surrounded by oil and
do not react readily with the effervescent components. With
the dissolution of the enteric coating 22 and barrier coating
22 (if used) , the core° of the tablet is exposed, facilitating
disintegration of the core, release of the emulsion droplets
from the adsorbent and subsequent drug release from the
emulsion.
A second design, which is illustrated in Figure 2,
includes agglomerates 10, each of which includes agglomerate
of multiple particles 12 of adsorbent, having adsorbed
emulsion 13 seen in a schematic representation in Fig. 2A.
The agglomerates are coated with an enteric material 14. The
coated agglomerates are then compressed together into a
relatively soft tablet 15, with fillers, flavors, sweeteners,
disintegrants and other excipients added. The compressed
tablet may include some interstitial spaces 16, which can be
filled with a filler. Such a tablet, which may be much larger
than a conventional tablet, is allowed to disintegrate within
the oral cavity. Disintegration, which usually occurs within
2 minutes, and more preferably within 1 minute, releases the
enteric-coated agglomerates which are swallowed. This enables
absorption to occur at a site distal to the oral cavity.
Absorption usually occurs in the duodenum. However, the
preparation can contain other components which promote
absorption at other sites such as, but not limited to, the
colon. This tablet may contain effervescence to aid
disintegration and palatability or may include enteric-coated
effervescent granules which promote absorption in the duodenum
or other targeted site.
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Particles may be manufactured by granulation (wet or dry
process), layering techniques, extrusion and spheronization or
other pellet manufacturing methods. Dry granulation may be
achieved through slugging or calcination of a powder mix
(including adsorbed emulsion) that has the appearance of a dry
powder. Layering may be done in a fluid bed apparatus or
coating pan. The fine powder with the adsorbed emulsion
(having the appearance of a dry powder) is layered onto the
starting material or cores. Aqueous or non-aqueous binders are
used to aid the adherence of the added material onto the
cores. The choice of binder is dictated, in part, by the
nature of the emulsion and the drug being utilized in a
particular preparation. The binder should be test for its
effect on drug stability. Only the binders which do not
negatively affect drug stability in the emulsion will be used.
Layering is preferably done in a fluidized bed coater. In
this apparatus, the bed of material remains wet for a very
short time and, hence, it is often possible to use a binder
that may, at first sight, appear incompatible. In addition to
the fine particle-adsorbed emulsion, other materials may be
layered onto the starting material. These include, without
limitation, the drug or additional amounts of the drug,
penetration enhancers, and other excipients. Nonlimiting
examples of the starting material or cores are nonpareils
(sucrose) or microcrystalline cellulose seeds. The size of
the multiparticulates is preferably up to about 3 mm. Coating
of the dosage forms or the multiparticulates may be
accomplished in a fluid bed coater or by other coating
techniques. The multiparticulates may be packed into
capsules.
Where a wet process, such as wet granulation or extrusion
and spheronization is used, the emulsion is, preferably, used
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as the liquid phase or granulating fluid. More preferably,
o/w emulsions are used as the liquid phase in the wet process
since this type of emulsion may be diluted with water to give
the correct consistency for processing with the solid
components and, furthermore, partial drying of the formed
particulates will result in a product that has a dry
appearance. Inclusion in the external aqueous phase of
water-miscible, non-toxic, volatile organic solvents such as,
for example, isopropyl alcohol, or ethyl alcohol may be
advantageous in facilitating the partial evaporation of the
external phase of the emulsion from the formed particulates.
A variation of this design is one in which the material
does not contain an enteric coat, but is retained in the oral
cavity where the drug is released for absorption by the oral
mucosa. When the latter design is utilized, the tablet may
contain additional penetration enhancers, mucoadhesives or
other agents to facilitate absorption in the oral cavity.
Tablets can be manufactured by wet granulation, dry
granulation, direct compression or any other tablet
manufacturing technique. Orally disintegrating tablets may be
relatively soft and are preferably made by direct compression
in accordance with the disclosures in U.S. Pat. No. 5,178,878,
which are hereby incorporated by reference herein. For
peptides and other biological molecule, low compression forces
are preferable because these substances are sensitive to
compression forces. With such compounds, the conformation of
the compound and the biological activity can change with the
higher compression forces that are conventionally used in
tablet manufacture.
The tablet may be a layered tablet consisting of a layer
of the active ingredients, set forth above, within layers of
diverse compositions. Alternatively, the tablet may be a
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simple tablet of uniform composition. In accordance with the
present invention, the tablet size is preferably up to about 3/4
inch. The tablet hardness is preferably between about 5
Newton ( "N" ) and about 50 N and more preferably between about
15N and 35N for an uncoated tablet. Tablets that intended are
to be coated, for example with an enteric coat, are preferable
slightly harder, having hardness values of 20N to 70N and more
preferably from 25N to 50N. These values relate to the
uncoated cores and, as expected, the hardness values of the
tablets increase due to the addition of the coating layer.
The tablet may be one that is intended for vaginal
administration in which case it, preferably, contains fine
particle powders as the filler and other excipients to reduce
the potential for physical irritation or abrasion. In
addition the tablet is of a special shape to facilitate
insertion into the vagina. Non-limiting examples of such
shapes include oval and diamond-shaped. The insertion of the
tablet may be facilitated by the use of a special applicator
device well known in the industry for this purpose.
Tablets containing the emulsion can be coated with an
enteric material. This is preferably done in a coating pan.
Many of the modern, perforated pans have features which make
for more efficient coating. As an example, the Hicoater
(Vector Corporation, Iowa) may be used. The tablets within
the pan are preheated and the pan is rotated at a rate that
allows gentle tumbling of the tablets. Many of the comments
regarding the actual process (such as rate of wetting of the
material) made for the fluidized bed coater, apply to the pan
coater as well. The coating solution should be non-aqueous
when effervescent material is incorporated within the
preparation and the effervescence preferably separated from
the emulsion by a coating.
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Precoating materials may also be used in the present
invention. Nonlimiting examples of precoating materials
include cellulose derivatives such as methylcellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose or
combinations and certain materials sold under the trademark
EUDRAGIT ~ (various grades which may be combined).
Excipients, such as fillers can be used in connection
with the present invention to facilitate tableting.
Nonlimiting examples of fillers include: mannitol, dextrose,
lactose, sucrose, and calcium carbonate. For a tablet
intended to disintegrate in the oral cavity, the mass of the
tablet should, preferably, not exceed 2.5 g. If an
effervescent agent is included, the effervescence level in the
tablet is preferably between about 5o and 65% by weight based
on the weight of the finished tablet.
The emulsion adsorbed onto a fine particle adsorbent may
be incorporated into a suppository formed, for example, by
molding. In this technique, the free-flowing powder is mixed
with the molten suppository bases) and poured into a mold and
allowed to set by cooling to ambient temperature. Suitable
suppository bases include, but are not limited to, cocoa
butter, polyethylene glycols, polyvinyl pyrrolidone, gelatin,
gelatin/glycerin combinations, esterified fatty acids,
polyoxyethylene sorbitans and polyoxyethylene sorbitan fatty
acid esters. Various proprietary bases which may contain
mixtures of different components are also available. Examples
of proprietary bases are those sold under the trade names
Imhausen, Witepsol and Gelucire. Various grades of each of
these are available for specific applications. Mixtures of
various bases may also be utilized in order to obtain a
suppository with the required properties.
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Various additives may be incorporated into the
suppositories of the present invention including surfactants
and absorption enhancers such as medium chain (C$ to C1~) fatty
acids and fatty acid esters including mono-, di-, and
triesters of glycerol. Other shaping methods for forming the
suppositories including cold molding and compression may also
be used.
It is preferable that the hydrophilic/ hydrophobic nature
of the suppository base be different from the external phase
of the emulsion i.e. where an o/w emulsion is used, the
suppository base should be a fatty (hydrophobic) base such as
cocoa butter; in the case of a w/o emulsion, the suppository
base should be hydrophilic such as, for example, a gelatin/
glycerin base. This helps to maintain the stability of the
emulsion by preventing the formation of a miscible mixture
between the external phase of the emulsion and the suppository
base.
Various publications are cited throughout this
application. These publications are hereby incorporated by
reference.
The invention will further be described by reference to
the following examples. These examples are provided for the
purpose of illustration only, and are not intended to be
limiting unless otherwise specified.
EXAMPLE 1: Preparation of oil-in-water emulsion
Ingredients Amount
Liquid paraffin 200 g
Lovostatin 79.523 g
Chloroform 1.2 g
Benzoic acid solution* 10 g
Methylcellulose 20 7 g
Water to 500 g
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*Benzoic acid solution consists of 5 g benzoic acid, 75 mL
propylene glycol and water to 100 mL. The emulsion contains
about 15.9% of the drug, Lovostatin.
Procedures of preparing emulsions:
The drug was dispersed in the liquid paraffin with
gentle heat and stirring. The aqueous phase was prepared
separately as follows. The methylcellulose was dispersed in
100 mL of hot water. An additional 120 mL of cold water was
added to this and stirred to form a homogeneous gel. The
chloroform was added to the benzoic acid solution slowly with
stirring and this mixture was added to the aqueous phase and
stirred.
The oil phase was added to the water phase and stirred
with a propeller stirrer. The emulsion was made up to 500 mL
by the addition of water. The formed emulsion was passed
several times through a homogenizer until the globules of oil,
as determined by observation using a microscope, were less
than 20 ~m in diameter. The technique for evaluating the
sizes of emulsion globules was described in publications such
as "A comparison of two quality assessment methods for
emulsions" by S. I. Pather, S.H. Neau and S. Pather, Journal
of Pharmaceutical and Biomedical Analysis 13 (1995) 1283-1289
which is hereby incorporated herein by reference.
EXAMPLE 2: Adsorption of emulsion onto silicon dioxide
Ingredients Amount in g
Emulsion (from example 1) 500
Colloidal Silicon dioxide 1500
Total 2000
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Procedures of adsorbing emulsion onto silicon dioxide: Place
colloidal silicon dioxide powder into the bowl of a planetary
mixer and add the emulsion slowly with continuous mixing to
obtain a powder that was dry to the touch.
EXAMPLE 3: Formula for tablets using oil-in-water emulsion
Ingredients mg/ tablet
o_ _
Emulsion/ Silicon dioxide (3:1) 251.5
50.3
(from example 2)
Prosolv 90 153.0
30.6
Spray dried lactose 55.0 11.0
Crospovidone 33.0
6.6
Magnesium Stearate 7.5
1.5
2p Total 500.0
100.0
Procedures for formulating tablets using oil-in-water
emulsion: Emulsion/ Silicon dioxide, Prosolv 90 (silicified
microcrystalline cellulose), Spray dried lactose, and
Crospovidone was weighed and screened into a blender and
blended for 30 minutes. Then, Magnesium Stearate was weighed
and added to the blender and blended a further 5 minutes. The
blend was discharged and compressed into tablets using 1/Z inch
punches.
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EXAMPLE 4: Coating solution formula
Ingredients g/batch
Hydroxypropyl methylcellulose phthalate (HP 55S) 372
Triethyl Citrate 28
Ethanol 1800
Acetone 1800
Total 4000
Procedure: The coating solution was prepared by adding HP 55S
to ethanol and acetone in a large beaker and stirring
vigorously. The mixture was stirred until the HP 55S had gone
into solution completely. Triethyl Citrate was then added and
stirred further to obtain the final solution used to coat
tablets produced in example 3. The coating was carried out in
a coating pan to limit loss of material from the tablets due
to friability. The airflow during the coating process was
maintained at 30 CMH (cubic meters/hr) and spray rate is 9.5
g/min. The pan speed was maintained at 20 rpm. The inlet air
temperature was maintained between 42 and 45 C and coating was
continued until a weight gain of 15% was obtained. Each of
the final tablet contains about l0mg of Lovostatin.
EXAMPLE 5. Preparation of Water-In-Oil Emulsion Formulation
Ingredients g/batch
Polyethylene glycol castor oil 300
Mineral oil 3,700
Propylene glycol 1,000
Water-soluble drug 500
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Water 4,500
The water-soluble drug in example 5 is calcitonine, or an
oligonucleotide, such as those having 8 to 12 base pairs.
Mix together the oil phase, i.e. polyethylene glycol
castor oil and mineral oil and heat to 75°C. Then mix together
the water phase ingredients, i.e. water, water-soluble drug
and propylene glycol and heat to 75°C. In preparing the water
phase, the water-soluble drug is preferably dissolved in
propylene glycol first and then this drug-propylene glycol
solution is added to water. Add the water phase to the oil
phase and mix thoroughly under vigorous stirring to form w/o
emulsion formulation. This w/o emulsion formulation is then
adsorbed onto silicon dioxide and the emulsion/adsorbent is
incorporated into a tablet as described in this application.
Drugs that would benefit from such treatment are
water-soluble but poorly absorbed drugs. The heat stability
of the drug must be taken into account when formulating in
this fashion. Tf the drug is dissolved in hot water and the
water phase is rapidly mixed with oil phase and then allowed
to cool, it may be possible to prepare the emulsion without
undue degradation of the drug. An overage of the drug may be
incorporated to accommodate the amount lost during heating and
mixing.
EXAMPLE 6: High Drug Loading in Emulsion Formulation
One hundred grams of Vitamin E Acetate (~-tocopherol
acetate) are emulsified with suitable emulsifying agents to
form approximately 2008 of an emulsion formulation per batch
of 1,000 tablets. This emulsion formulation contains about
fifty percent of Vitamin E Acetate. This emulsion formulation
is adsorbed onto approximately 6008 of silicon dioxide. The
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silicon dioxide with adsorbed emulsion formulation is
incorporated into 1,000 orally disintegrating tablets which
has a total mass of approximately 2,4008, using suitable
direct compression ingredients. The emulsion has a pleasant
taste which is not "oily." The fact that the liquid is
adsorbed further contributes to the pleasant organoleptic
experience of the person consuming this preparation.
Additional flavoring and sweetening agents may also be
incorporated into the product.
These tablets are convenient to take, especially for
those patients who do not like to take capsules. In addition,
it may offer enhanced absorption by the patient's body because
the emulsified droplets of vitamin E acetate are adsorbed onto
fine particles which may then become distributed over a large
area of the gastrointestinal tract. The larger surface area
available for absorption allows for more efficient absorption.
Example 7: Medium Drug Loading
Ingredients Amount
Liquid paraffin 200 g
Chloramphenicol 200 g
Chloroform 1.2 g
Benzoic acid solution* 10 g
Methylcellulose 20 7 g
Water to 500 g
The emulsion is prepared in the same way as in example 1.
The final drug content in the emulsion is about 400.
Example 8: Low Drug Loading
Ingredients Amount
Liquid paraffin 120 g
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Dexamethasone 10 g
Chloroform 1.2 g
Benzoic acid solution* 10 g
Methylcellulose 20 4 g
Water to 500 g
The product is prepared in a similar fashion to the
lovostatin tablets (example 1) but each tablet will contain
0.5 mg dexamethasone. The emulsion contains about of drug,
dexamethasone. The 5008 of emulsion is again adsorbed
onto
about 1,5008 of silicon dioxide. Since the emulsion contains
sufficient drug for 20,000 tablets, only 100 mg of the
emulsion/ solid support mixture need be used per tablet.
The
15 mass of the tablet is 500 mg. The lower loading of
emulsion/
solid support per tablet makes it easier to produce suitable
a
tablet. Obviously if slightly more than 1,5008 of silicon
dioxide is used in the adsorption step, the amount mixture
of
per tablet would be slightly more.
20 EXAMPLE 9: Preparation of SEDDS
Ingredients Amount
Liquid paraffin 200 g
Lovostatin 80 g
Chloroform . 1 g
Benzoic acid solution* 9 g
Methylcellulose 20 7 g
A1203 400 g
The oil phase containing Lovostatin is prepared in the
same way as in example 1. The oil phase is then adsorbed onto
the A1203 particles in the form of oil droplets or oil film.
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Example 10: Suppository.
Fifty milligrams of testosterone enantate is dissolved in
0.25 m1 sesame oil (per suppository). Using suitable
emulsifying agents the oil is converted into approximately 0.5
ml of an o/w emulsion. This is adsorbed onto approximately
0.8 g of silicon dioxide which is incorporated into a
hydrophobic suppository base, such as
hydrogenatedtriglyceride. Suppositories each weighing
approximately 2g are molded from this mixture. Upon
administration, the suppository melts and the emulsion on the
solid support is dispersed in the rectal fluids. This aids in
absorption, while this mode of administration eliminates
painful injections.
As used herein, suppositories include, but are not limited to
the following:
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Suppository Bases
Adeps Solidus
Triglycerides of saturated fatty
Cebes Pharma 16 acids with mono- and diglycerides
Cotomar Modified palm kernel oil
S-70-XX95, X70-XXA Partially hydrogenated cottonseed oil
Hydrokote Rearranged hydrogenated vegetable
oils
Idropostal (water Higher melting fractions of coconut
soluble) and palm kernel oil; upon request,
may contain 0.250 lecithin
Kaomel
Condensation product of polyethylene
Massa Estarinum (oxide
Fractionated Hydrogenated
Triglycerides
Massa Mf 13 (fat
soluble) Mixture of tri-, di-, and
monoglycerides of saturated fatty
acids
Neosuppostal-N C11Ha3C00H to C1~H35COOH
Mixture of di- and triglycerides of
Paramount B saturated fatty acids
Satina III . Hydrogenated triglyceride with fatty
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alcohols and emulsifiers
Suppocire
Hydrogenated interesterified
vegetable oils
Novata
Fractionated hydrogenated
Suppostal triglycerides
Eutectic mixtures of mono-, di-, and
Wecobee W triglycerides derived from natural
vegetable oils
Wecobee R
Mixture of tri-, di-, and
monoglycerides of saturated fatty
acids
Witepsol
Hydrogenated triglyceride with fatty
alcohols and emulsifiers
Tween 61
Triglycerides
Higher melting fractions of coconut
oil and palm kernel oil (may contain
0.250 lecithin)
Triglyceride of saturated vegetable
fatty acids with monoglycerides
(formerly marketed as "Imhausen
bases")
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Polyethylene glycol sorbitan
monostearate
Versatility of Emulsions Compared to Microemulsions
Examples 7 to 8 above illustrate the versatility of
emulsions in delivering drugs in comparison to microemulsions.
To prepare a suitable emulsion for the low dose drug, a
formulator can take the emulsion for the high dose (which
required a high volume of oil for dispersion of the larger
amount of drug) and modify it easily for the low dose drug.
Since less oil is needed in low dosage drug, less emulsifying
agent is added. These changes, i.e. from high dosage drug to
low dosage drug, decrease the viscosity of the emulsion and
make it easier for the formulator to handle. This
interchangeability between high dosage drug and low dosage
drug formula can easily be made using emulsion by one of
ordinary skill in the art. In fact, an emulsion formula can
be altered much more "at will".
By contrast, microemulsions have a fixed formulation and
thus, can only be varied within a narrow range. Usually, the
volume of the internal phase (oil in this example) cannot be
varied by much. In order to know how much the microemulsion
formula can be varied and yet remain a microemulsion, the
formulator would have to prepare several formulations and plot
triangular phase diagrams to obtain the zones in which a
microemulsion exists. The triangular phase diagram has to be
determined for each particular system and it is a time
consuming task.
