U.S. patent application number 10/303197 was filed with the patent office on 2003-04-24 for emulsions as solid dosage forms for oral administration.
Invention is credited to Gupte, Sangeeta V., Hontz, John, Khankari, Rajendra K., Kumbale, Ramya, Pather, S. Indiran.
Application Number | 20030077306 10/303197 |
Document ID | / |
Family ID | 25157636 |
Filed Date | 2003-04-24 |
United States Patent
Application |
20030077306 |
Kind Code |
A1 |
Pather, S. Indiran ; et
al. |
April 24, 2003 |
Emulsions as solid dosage forms for oral administration
Abstract
Novel emulsion compositions which improve the rate and/or extent
of absorption of drugs are disclosed. The novel emulsion
compositions of the present invention include drug-containing
emulsions adsorbed onto solid particles which may be further
formulated into solid dosage forms, methods of preparing such
emulsion compositions and their uses thereof. The emulsion
compositions and their dosage forms improve the drug-load and the
bioavailability of a wide range of drugs including drugs that are
known or suspected of having poor bioavailability by the
utilization of several different mechanisms.
Inventors: |
Pather, S. Indiran;
(Plymouth, MN) ; Gupte, Sangeeta V.; (Vernon
Hills, IL) ; Khankari, Rajendra K.; (Maple Grove,
MN) ; Hontz, John; (Plymouth, MN) ; Kumbale,
Ramya; (Morris Plains, NJ) |
Correspondence
Address: |
LERNER, DAVID, LITTENBERG,
KRUMHOLZ & MENTLIK
600 SOUTH AVENUE WEST
WESTFIELD
NJ
07090
US
|
Family ID: |
25157636 |
Appl. No.: |
10/303197 |
Filed: |
November 25, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10303197 |
Nov 25, 2002 |
|
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09792659 |
Feb 23, 2001 |
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Current U.S.
Class: |
424/400 ;
424/465 |
Current CPC
Class: |
A61K 9/143 20130101 |
Class at
Publication: |
424/400 ;
424/465 |
International
Class: |
A61K 009/00; A61K
009/20 |
Claims
1. An emulsion composition comprising: a free-flowing, compressible
particle which is an admixture of a drug-containing emulsion having
a viscosity of between about 1 cps and about 400,000 cps and
wherein said emulsion has globules having diameters of greater than
100 nm.
2. The emulsion composition of claim 1, wherein the drug-containing
emulsion has a viscosity of between about 400 cps and about 200,000
cps.
3. The emulsion composition of claim 1, wherein the drug-containing
emulsion having between about 2% and about 50% drug by weight based
on the weight of the formulation.
4. The emulsion composition of claim 1, wherein said
drug-containing emulsion is an oil-in-water emulsion.
5. The emulsion composition of claim 1 wherein said drug-containing
emulsion is a water-in-oil emulsion.
6. The emulsion composition of claim 1, wherein said
drug-containing emulsion is a self-emulsifying drug delivery system
which converts to an emulsion in vivo.
7. The emulsion composition of claim 1, wherein said solid particle
is selected from the group consisting of kaolin, bentonite,
hectorite, colloidal magnesium aluminum silicate, silicon dioxide,
magnesium trisilicate, aluminum hydroxide, magnesium hydroxide,
magnesium oxide and talc.
8. The emulsion composition of claim 1, wherein the compressibility
of the free-flowing compressible powder is further improved by the
addition of direct compression tableting excipients.
9. The emulsion composition of claim 1, wherein said drug contained
in said emulsion is a drug that displays poor bioavailability in
the gastrointestinal tract of a mammal, when said drug is
administered in a conventional dosage form that does not contain
any penetration enhancer or other mechanism to enhance drug
absorption.
10. The emulsion composition of claim 1, wherein said
drug-containing emulsion includes a drug selected from the group
consisting of peptides, proteins, oligonucleotides and other
biological molecules.
11. The emulsion composition of claim 1, wherein said
drug-containing emulsion includes a nutritional supplement.
12. The emulsion composition of claim 1, wherein said
drug-containing emulsion includes a drug selected from the group
consisting of acyclovir; auranofin; bretylium; cytarabine; doxepin;
doxorubicin; hydralazine; ketamine; labetalol; mercaptopurine;
methyldopa; nalbuphine; nalozone; pentoxifylline; pryridostigmine;
terbutaline; verapamil; buserelin; calcitonin; cyclosporin;
heparin; and oxytocin.
13. An emulsion composition comprising: a free flowing,
compressible particle which is an admixture of a drug-containing
emulsion having between about 2% and about 50% drug by weight based
on the weight of the finished formulation, said emulsion having
globules having diameters of greater than 100 nm.
14. The emulsion composition of claim 13, wherein said emulsion has
a viscosity of between 1 cps and 400,000 cps.
15. The emulsion composition of claim 14, wherein said emulsion has
a viscosity of between about 120 nm and 70 .mu.M.
16. The emulsion composition of claim 13, wherein said particle is
an absorbent powder and wherein said drug-containing emulsion is
adsorbed on said particle.
17. A solid dosage form for the administration of a therapeutically
effective amount of a drug, comprising: the emulsion composition of
claims 1 or 13 and, optionally, at least one filler.
18. The solid dosage form of claim 17, wherein said solid dosage
form is a tablet for oral administration.
19. The solid dosage form of claim 17, wherein said solid dosage
form is a capsule for oral administration.
20. The solid dosage form of claim 17, wherein said solid dosage
form is a tablet for intra-oral administration, wherein said tablet
is allowed to disintegrate in the oral cavity of a mammal, wherein
the constituents of the tablet can be swallowed without the
consumption of water or other liquid to assist swallowing.
21. The solid dosage form of claim 17, further comprising a
bioadhesive.
22. The solid dosage form of claim 17, wherein said solid dosage
form is a tablet for vaginal administration.
23. The solid dosage form of claim 17, wherein said sold dosage
form is a suppository for vaginal administration.
24. The solid dosage form of claim 17, wherein said solid dosage
form is a suppository for rectal administration.
25. The solid dosage form of claim 17, further comprising an
enteric coating maintained over said dosage form; wherein said
enteric coating prevents the release of said drug-containing
emulsion until a time at which said dosage form reaches a target
area following oral administration.
26. The solid dosage form of claim 25, wherein the enteric coating
is selected from materials of the group consisting of a methacrylic
acid copolymer, sugar, gelatin, hydroxypropyl cellulose or
hydroxypropylmethyl cellulose phthalate, cellulose acetate
phthalate, polyvinylacetate phthalate, methacrylic acid copolymer,
shellac, hydroxypropylmethylcellul- ose succinate, cellulose
acetate trimellitate, and their mixtures thereof.
27. The solid dosage form of claim 17, wherein said solid dosage
form further comprises at least one effervescent agent.
28. The solid dosage form of claim 17, further comprising at least
one disintegration agent; wherein said disintegration agent causes
rapid dispersion of said drug-containing emulsion to a target area
following oral administration.
29. The solid dosage form of claim 17, further comprising a pH
adjusting substance.
30. The solid dosage form of claim 17, wherein said drug-containing
emulsion includes a drug selected from the group consisting of
peptides, proteins, oligonucleotides and other biological
molecules.
31. The solid dosage form of claim 17, wherein said drug-containing
emulsion includes a nutritional supplement.
32. The solid dosage form of claim 17, wherein said drug-containing
emulsion includes a drug selected from the group consisting of
acyclovir; auranofin; bretylium; cytarabine; doxepin; doxorubicin;
hydralazine; ketamine; labetalol; mercaptopurine; methyldopa;
nalbuphine; nalozone; pentoxifylline; pryridostigmine; terbutaline;
verapamil; buserelin; calcitonin; cyclosporin; heparin; and
oxytocin.
33. The solid dosage form of claim 17, further comprising at least
one filler, disintegration agent, effervescent agent or a pH
adjusting substance.
34. The solid dosage form of claim 33, wherein said drug is
selected from the group consisting of acyclovir; auranofin;
bretylium; cytarabine; doxepin; doxorubicin; hydralazine; ketamine;
labetalol; mercaptopurine; methyldopa; nalbuphine; nalozone;
pentoxifylline; pryridostigmine; terbutaline; verapamil; buserelin;
calcitonin; cyclosporin; heparin; and oxytocin.
35. A method for preparing an emulsion composition, comprising the
steps of: preparing a drug-containing emulsion and converting said
drug-containing emulsion into a free-flowing, compressible powder
by admixing said drug-containing emulsion with a solid
particle.
36. A method for preparing a solid dosage form for the oral
administration of a therapeutically effective amount of a drug,
comprising the steps of: preparing a drug-containing emulsion
having a viscosity of between about 1 cps and about 400,000 cps and
wherein said emulsion globules has diameters of greater than 100
nm; converting said drug-containing emulsion into a solid by
admixing said drug-containing emulsion with solid particles and
compressing said solid, with the optional addition of an excipient,
into a solid dosage form.
37. A stable emulsion composition which is the product of the
process of: preparing a drug-containing emulsion; converting said
drug-containing emulsion into a powder by admixing said
drug-containing emulsion with a solid particulate adsorbent.
38. A method of administering an emulsion composition of claims 1
or 13 to a mammal comprising the steps of preparing the emulsion
composition of claims 1 or 13 and administering said emulsion
composition to said mammal.
39. A method is claimed in claim 38 further comprising the step of
incorporating said emulsion composition into a solid dosage form,
said step of administering said emulsion composition to said mammal
including the step of administering the solid dosage form to the
mammal.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional application of U.S.
application Ser. No. 09/792,659, filed Feb. 23, 2001, the
disclosure of which is incorporated by reference herein.
FIELD OF THE INVENTION
[0002] 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
[0003] 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
(25%) with a range of 8% to 62%; and nalbuphine (approximately 17%)
with a range of 6% to 40%.
[0004] 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 passively, dissolution of the drug is the first step in the
absorption process.
[0005] 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.
[0006] 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. 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. With 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.
[0007] 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. 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.
[0008] Unfortunately, the application of powder solution technology
has been limited.
[0009] 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 Ser. No.
09/374,393 and the corresponding international application
PCT/US99/18552 published under Pub. No. WO009093A1 is incorporated
herein by reference.
SUMMARY OF THE INVENTION
[0010] 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 2% and 50% active drug
ingredient, preferably between 5% and 40% and more preferably
between 10% and 30%.
[0011] 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 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.
[0012] 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.
[0013] 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.
[0014] Administration of drugs in the above-mentioned dosage forms
offers significant advantages over the previously available methods
of administration.
[0015] 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 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.
[0016] 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 (o/w)
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 in vivo agglomeration
is retarded, absorption can be facilitated.
[0017] 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 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.
[0018] 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.
[0019] 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).
[0020] 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 ("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 adsorbent particles are
administered and in contact with the body fluid, they form an
emulsion composition.
[0021] 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.
[0022] 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.
[0023] 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 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
[0024] FIG. 1 is an enlarged top plan view of a tablet according to
one embodiment of the invention.
[0025] FIG. 2A is a cross-section view of a tablet according to
another embodiment of the invention.
[0026] FIG. 2B is a schematic diagram for the preparation of a soft
tablet.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] 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.
[0028] 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-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. After
administration of the emulsion compositions containing SEDDS, an
emulsion forms in vivo upon admixing with the body fluids.
Generally, emulsions can also be classified as fine emulsions with
globule diameters of less than 5 .mu.m and coarse emulsion with
globule diameters greater than 5 .mu.m.
[0029] The oil phase in the emulsion can be any nontoxic oil, which
includes, but is 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
chain of C.sub.8 to C.sub.12 and short chain is a hydrocarbon chain
of less than C.sub.8 and long chain means a hydrocarbon chain of
more than C.sub.12.
[0030] The water phase in the emulsion can be water, aqueous
solutions, alcohols, alcohol solutions, etc.
[0031] 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. The oils include, but are not limited
to, natural oils, such as cottonseed oil, soybean oil, sunflower
oil; canola oil; CAPTEX.RTM. (various grades Propylene Glycol
Esters such as Propylene Glycol didecanoate; and Glycerol esters
such as Glyceryl tricaprylate/caprate); MIGLYOL.RTM.
(Caprylic/capric acid triglycerides; or Caprylic/capric/linoleic
acid triglycerides; or Caprylic/capric/succinic acid triglycerides;
or Propylene glycol diester of caprylic/capric acid and admixtures
with other agents); CAPMUL.RTM. (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.).
[0032] 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:
MYVACET.RTM. (distilled acetylated monoglyceride emulsifers);
ARLACEL.RTM. (mainly sorbitan esters); TWEEN.RTM. (polyoxyethylene
sorbitan esters); CENTROPHASE.RTM. (fluid lecithins);
CREMOPHOR.RTM. (polyoxyl castor oil derivatives; or macrogol
ethers; or macrogol esters); LABRAFAC.RTM. (caprylic/capric
triglyceride); LABRAFIL.RTM. (polyoxyethylated glycolysed
glycerides); LABRASOL (mixture of mono-, di- and triglycerides and
mono-and di-fatty esters of polyethylene glycol. The predominant
fatty acids are C.sub.8-C.sub.10 caprylic/capric acids);
MYVEROL.RTM.; and TAGAT.RTM. (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.
[0033] 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 non-toxic and
compatible with the part of the mammalian body to which they are to
be applied, may be used.
[0034] 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%.
[0035] 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%.
[0036] 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 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.
[0037] 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.
[0038] The 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.
[0039] 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 subject 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 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.
[0040] 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.
[0041] 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 this would affect the
bioavailability of the drug, in general.
[0042] Any active substance (drug) may be used in the emulsion.
Liquid drugs, drug solutions, small molecule drugs and nutritional
supplements, such as vitamins and minerals, are suitable for use in
the present invention.
[0043] 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.
[0044] Preferably, the drug is chosen from one or more of the
following categories/groups: abortifacient/interceptive,
ace-inhibitor, .alpha.-adrenergic agonist, .beta.-adrenergic
agonist, .alpha.-adrenergic blocker, .beta.-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, 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, anxiolytic,
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, .alpha.-glucosidase inhibitor, gonad-stimulating
principle, gout suppressant, growth hormone inhibitor, growth
hormone releasing factor, growth stimulant, hematinic,
hematopoietic, hemolytic, hemostatic, heparin antagonist,
hepatoprotectant, histamine H.sub.1-receptor antagonist, histamine
H.sub.2-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, 5.alpha.-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 A.sub.2-receptor antagonist, thromboxane
A.sub.2-sythetase inhibitor, thyroid hormone, thyroid inhibitor,
thyrotropic 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.
[0045] 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.
[0046] Generally, the drug-containing emulsion contains between
0.5% and 60% active drug ingredient. The active drug ingredient is
preferably in the range of between 2% and 50% of the total weight
of the drug-containing emulsion (both phases), more preferably
between 5% and 40% and most preferably between 10% and 30%. 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.
[0047] The emulsions are also suitable for the administration of
active substances that display poor bioavailability, slow
absorption or long t.sub.max. 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.
[0048] As used herein, the phrase "biological molecule" includes,
but is not limited to polypeptides, DNA molecules, RNA molecules,
polysaccharides, etc.
[0049] 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.
[0050] 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 .mu.m or 100 nm, particularly in the
range of 0.16 .mu.m to 40 .mu.m, while microemulsions contain
globules having diameter of less than 0.1 .mu.m. 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:
[0051] 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
microemulsions 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.degree. C.
[0052] The physical appearances of microemulsion and emulsion are
different. Microemulsions are transparent (like water) because the
globules in microemulsions are too small to refract light.
Emulsions are usually white or cream in color.
[0053] Microemulsions 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 phases, 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 is
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, dispersion of the emulsion on the adsorbent retards
coalescence of the interior phase globules with one another.
[0054] 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).
[0055] In a preferred embodiment of the invention, the
drug-containing emulsion comprises emulsion globules having mean or
modal diameters of greater than 100 nm, preferably between 120 nm
and 70 .mu.m, and more preferably between 160 nm and 10 .mu.m. The
drug containing emulsion of the emulsion composition is preferably
stable for at least one year when left in a closed container at
25.degree. 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 vivo.
[0056] 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 .mu.m, preferably in
the range of 50 nm to 30 .mu.m and more preferably in the range of
100 nm to 20 .mu.m. Suitable adsorbents include, but are not
limited to, clays such as kaolin, bentonite, hectorite and
colloidal magnesium aluminum silicate; silicon dioxide (CAB-O-SIL"
or AEROSIL.RTM.); magnesium trisilicate; aluminum hydroxide;
magnesium hydroxide, magnesium oxide or talc. More preferably the
adsorbent is silicon dioxide.
[0057] 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.
[0058] 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.
[0059] 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.
[0060] 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 compressible blend. This compressible blend
should be free flowing.
[0061] 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.
[0062] 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.
[0063] 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 1,000 mg of active
drug ingredient/tablet (of e.g. 2.4 grams), preferably between 5 mg
and 500 mg, more preferably between 10 mg and 200 mg and the most
preferably between 15 mg and 100 mg.
[0064] Coating can also be applied to the individual particles of
the emulsion composition powder; to agglomerates, granules 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.RTM. (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.
[0065] 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. 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.
[0066] 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.
[0067] 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 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.
[0068] 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 S100 (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.
[0069] 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 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.
[0070] 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.
[0071] 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
emulsion compositions prepared by the method are also
contemplated.
[0072] 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.
[0073] 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
and 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
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.
[0074] 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
methylcellulose, methylcellulose, polycarbophil (Noveon AA-1),
hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium
alginate, and sodium hyaluronate.
[0075] 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.
[0076] Apart from the effervescent material within the tablet, some
additional effervescent components or, alternatively, only sodium
bicarbonate (or other alkaline substance) may be present in the
coating around the dosage form.
[0077] The purpose of the latter effervescent/alkaline material is
to react within the stomach contents and promote faster stomach
emptying.
[0078] Additionally, pH-adjusting substances, as described in U.S.
patent application Ser. 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.
[0079] 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
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.
[0080] A second design, which is illustrated in FIG. 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.
[0081] 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 chilsonation 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 tested 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.
[0082] Where a wet process, such as wet granulation or extrusion
and spheronization is used, the emulsion is, preferably, used 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.
[0083] 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.
[0084] 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.
[0085] 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 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 Newton ("N") and about 50 N and more
preferably between about 15N and 35N for an uncoated tablet.
Tablets that are intended 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.
[0086] 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.
[0087] 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.
[0088] 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.RTM. (various
grades which may be combined).
[0089] 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 5% and 65% by
weight based on the weight of the finished tablet.
[0090] 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 base(s) 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.
[0091] Various additives may be incorporated into the suppositories
of the present invention including surfactants and absorption
enhancers such as medium chain (C.sub.8 to C.sub.12) 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.
[0092] 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.
[0093] Various publications are cited throughout this application.
These publications are hereby incorporated by reference.
[0094] 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
[0095]
1 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 *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.
[0096] Procedures of preparing emulsions:
[0097] 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.
[0098] 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 .mu.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
[0099]
2 Ingredients Amount in g Emulsion (from example 1) 500 Colloidal
Silicon dioxide 1500 Total 2000
[0100] 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
[0101]
3 Ingredients mg/tablet % w/w 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 Total
500.0 100.0
[0102] 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 1/2 inch punches.
EXAMPLE 4
Coating Solution Formula
[0103]
4 Ingredients g/batch Hydroxypropyl methylcellulose phthalate (HP
55S) 372 Triethyl Citrate 28 Ethanol 1800 Acetone 1800 Total
4000
[0104] 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 was 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 final tablet contains about 10 mg of
Lovostatin.
EXAMPLE 5
Preparation of Water-In-Oil Emulsion Formulation
[0105]
5 Ingredients g/batch Polyethylene glycol castor oil 300 Mineral
oil 3,700 Propylene glycol 1,000 Water-soluble drug 500 Water
4,500
[0106] The water-soluble drug in example 5 is calcitonin, 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.degree. C. Then mix together the water
phase ingredients, i.e. water, water-soluble drug and propylene
glycol and heat to 75.degree. 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.
[0107] 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.
If 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
[0108] One hundred grams of Vitamin E Acetate (.alpha.-tocopherol
acetate) are emulsified with suitable emulsifying agents to form
approximately 200 g 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 600 g of silicon dioxide. The silicon dioxide with
adsorbed emulsion formulation is incorporated into 1,000 orally
disintegrating tablets which has a total mass of approximately
2,400 g, 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.
[0109] 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
[0110]
6 Ingredients Amount Liquid paraffin 200 g Chloramphenicol 200 g
Chloroform 1.2 g Benzoic acid solution 10 g (as in example 1)*
Methylcellulose 20 7 g Water to 500 g
[0111] The emulsion is prepared in the same way as in example 1.
The final drug content in the emulsion is about 40%.
EXAMPLE 8
Low Drug Loading
[0112]
7 Ingredients Amount Liquid paraffin 120 g Dexamethasone 10 g
Chloroform 1.2 g Benzoic acid solution 10 g (as in example 1)*
Methylcellulose 20 4 g Water to 500 g
[0113] 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 2% of drug,
dexamethasone. The 500 g of emulsion is again adsorbed onto about
1,500 g 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 mass of the tablet is 500 mg.
The lower loading of emulsion/solid support per tablet makes it
easier to produce a suitable tablet. Obviously if slightly more
than 1,500 g of silicon dioxide is used in the adsorption step, the
amount of mixture per tablet would be slightly more.
EXAMPLE 9
Preparation of SEDDS
[0114]
8 Ingredients Amount Liquid paraffin 200 g Lovostatin 80 g
Chloroform 1 g Al.sub.2O.sub.3 400 g
[0115] The oil phase containing Lovostatin is prepared in the same
way as in example 1. The oil phase is then adsorbed onto the
Al.sub.2O.sub.3 particles in the form of oil droplets or oil
film.
EXAMPLE 10
Suppository
[0116] Fifty milligrams of testosterone enantate is dissolved in
0.25 ml 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 hydrogenated triglyceride. Suppositories each weighing
approximately 2 g 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:SUPPOSITORY BASES
[0117]
9 Adeps Solidus Triglycerides of saturated fatty acids with mono-
and diglycerides Cebes Pharma 16 Modified palm kernel oil Cotomar
Partially hydrogenated cottonseed oil S-70-XX95, Rearranged
hydrogenated vegetable oils X70-XXA Hydrokote Higher melting
fractions of coconut and palm kernel oil; upon request, may contain
0.25% lecithin Idropostal Condensation product of polyethylene
oxide (water soluble) Kaomel Fractionated Hydrogenated
Triglycerides Massa Estarinum Mixture of tri-, di-, and
monoglycerides of saturated fatty acids C.sub.11H.sub.23COOH to
C.sub.17H.sub.35COOH Massa Mf 13 Mixture of di- and triglycerides
of saturated (fat soluble) fatty acids Neosuppostal-N Hydrogenated
triglyceride with fatty alcohols and emulsifiers Paramount B
Hydrogenated interesterified vegetable oils Satina III Fractionated
hydrogenated triglycerides Suppocire Eutectic mixtures of mono-,
di-, and triglycerides derived from natural vegetable oils Novata
Mixture of tri-, di-, and monoglycerides of saturated fatty acids
Suppostal Hydrogenated triglyceride with fatty alcohols and
emulsifiers Wecobee W Triglycerides Wecobee R Higher melting
fractions of coconut oil and palm kernel oil (may contain 0.25%
lecithin) Witepsol Triglyceride of saturated vegetable fatty acids
with monoglycerides (formerly marketed as "Imhausen bases") Tween
61 Polyethylene glycol sorbitan monostearate
[0118] Versatility of Emulsions Compared to Microemulsions
[0119] 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".
[0120] 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.
* * * * *