Note: Descriptions are shown in the official language in which they were submitted.
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
PHARMACEUTICAL FORMULATIONS CONTAINING METFORMIN
RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application No.
60/780,944 filed
on March 9, 2006, the contents of which are incorporated in their entirety by
reference.
FIELD OF INVENTION:
The present invention relates to combination compositions of pharmaceutical
therapeutics and the process of making the same. In particular, the present
invention relates
to metformin and salts thereof essentially combined with other commonly known
oral anti-
diabetic compounds. This combination composition can be formulated in an
instant release
formulation or granulated and combined with an extended release polymer and
further
dispersed in a rate-controlling matrix.
BACKGROUND OF INVENTION
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia,
insulin
resistance, and is often associated with other disorders such as obesity,
hypertension,
hyperlipidemia, as well as complications such as cardiovascular disease,
retinopathy,
neuropathy, and nephropathy. The disease is progressive in nature, and can
often be
controlled initially by diet alone, but 'generally requires treatment with
drugs such as
sulfonylureas and as the disorder progresses injections of exogenous insulin.
Another agent
known as a biguanide also is used to decrease hepatic glucose production as
well as intestinal
absorption of glucose. It has now been discovered that combination therapy
with a biguanide
and a sulfonylreas results in dramatic improvement in glycemic control, and
that even better
control and patient compliance can be achieved by using a combination
comprised of a
biguanide, and a sulfonylurea. Accordingly, such combinations are especially
useful in
treating diabetes and associated complications.
SUMMARY OF THE INVENTION
This invention provides a method of treating diabetes by administering to a
subject in
need of treatment a single dosage form having a combination of a sulfonylurea
together with
a biguanide anti-diabetic agent such as metformin. The sulfonylureas are a
class of
compounds that have been widely employed to treat diabetes. Such compounds are
well
1
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
known, for example as described in U.S. Pat. Nos. 3,454,635, 3,669,966,
2,968,158,
3,501,495, 3,708,486, 3,668,215, 3,654,357, and 3,097,242, all of which are
incorporated in
their entirety by reference. Preferred sulfonylureas to be employed in the
combinations of
this invention are glyburide, gliquidone, glipizide, tolbutamide, tolazamide,
glisoxepid,
chlorpropamide, glibornuride, gliclazide, glimepiride, phenbutamide, and
tolcyclamide.
According to this invention, the foregoing sulfonylureas are used in
combination with a
biguanide to treat diabetes with improved patient compliance thereby improving
glycemic
control.
Metformin Hydrochloride (N, N-dimethylimidodicarbonimidic diamide
hydrochloride) is a white to off-white crystalline compound with a molecular
formula of
C4HtiN5=HCl and a molecular weight of 165.63. It is freely soluble in water
and is
practically insoluble in acetone, ether, and chloroform. Metformin is a
biguanide that is not
chemically or pharmacologically related to any other classes of oral anti-
hyperglycemic
agents. It is absorbed mainly from the small intestine.
Metformin is stable in vivo and it does not bind to plasma proteins and is
therefore
excreted unchanged in the urine. It has a half-life of 1.3 to 4.5 hours. The
maximum
recommended daily dose of metformin is about 4 gms. Metformin is anti-
hypererglycemic
and it improves glucose tolerance in patients with type II diabetes, lowering
both basal and
postprandial plasma glucose. Unlike sulfonylureas, metformin does not produce
hypoglycemia in either patients with type II diabetes or normal subjects.
Hence it is a drug of
choice in controlling type II diabetes and is widely prescribed by physicians
all over the
world. It is presented in both instant release and extended release
formulations. The
extended release formulations have been developed to increase patient
compliance.
The present invention addresses the problems with patient compliance with
biguamide, such as metformin in combination with other orally active
hypoglycemic agents
used in combination therapy and provides a single formulation composition of
metformin and
in combination with a sulphonylurea, eg tolbutamide, chlorpropamide,
tolazamide,
glibenclamide, glyburide, glipizide, glimepiride or glicazide, which improves
patient
compliance with the convenience of a single formulation. In particular in a
preferred
combination according to the invention is metformin in combination with
glimepiride. In a
further preferred combination according to the invention the metformin in
combination with
glimepiride is formulated in an extended release formulation.
2
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
Glimepiride is an oral blood-glucose lowering drug of the sulfonylureas
'class.
Glimepiride is a white to yellowish-white crystalline, odorless to practically
odorless powder
that can be incorporated into combination tablets in doses of 1 mg, 2mg and
4mg strengths
for oral administration. Glimepiride can be administered up to 8mg per day in
divided doses
or up to 8mg in an extended release formulation. Chemically, glimepiride is
identified as
1 { {p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-
carboxamido)ethyl]phenyI]sulfonyl]-3-(trans-
4-methylcyclohexy)urea. The primary mechanism of action of glimepiride in
lowering blood
glucose appears to be dependent on stimulating the release of insulin from
functioning
pancreatic beta cells. In addition, extrapancreatic effects may also pay a
role in the activity of
sulfonylureas such as glimepiride.
According to an aspect of the present invention, there is provided a method of
treatment of hyperglycemic patients comprising administering the tablets
having a
combination of orally active hypoglycemic agents of varied doses made
according to the
invention in divided doses or in an extended release formulation once daily to
patients in
need thereof.
It is thus a further object of the present invention to provide instant
release or
controlled release compositions of metformin in combination with other orally
active
hypoglycemic agents or a pharmaceutically acceptable salts thereof.
A further object of the present invention is to provide controlled or instant
release
compositions of metformin and other orally active hypoglycemic agents that are
simple to
manufacture without involving cost intensive methods of preparation.
Another object of the present invention is to provide controlled or instant
release
compositions of metformin in combination with other orally active hypoglycemic
agents that
are simple to manufacture and have good compressibility that results in good
hardness tablets
that can withstand the rigors of coating.
DETAILED DESCRIPTION:
Although biguanides such as phenformin or buformin or pharmaceutically
acceptable
salts thereof, may be used for the purpose of the this invention, the
preferred drug, having
high water solubility for use herein is metformin or pharmaceutically
acceptable salts such as
metformin hydrochloride, metformin fumarate, and metformin succinate.
Metformin can be
used in varying doses such as 500 mg, 750 mg, 850 mg, and 1000 mg in instant
release
formulations and up to 4000mg per day in extended release formulations. It is
contemplated
3
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
within the scope of the invention that where desired, metformin or a salt
thereof may be used
in combination with another antihyperglycemic agent, which may be administered
orally in
the same dosage form in accordance with the present invention.
The present composition according to the invention can be either an instant
release
formulation or a controlled release formulation which is essentially comprised
of one or more
binders in an amount within the range of from with about 0.1% to about 10%
binder ,
preferably about 0.2% to about 5 % 2-4% binder and most preferably about 0.25%
to about
4.5% binder by weight of the composition. Binders usually are low viscosity
polymers or
non-polymeric materials and therefore they do not extend the release of a
drug. Although
binders improve appearance, hardness & friability of the preparation they are
usually not
intended to influence the disintegration or dissolution roles of active
substance.
Binders which are suitable for use herein include but are not limited to
copovidone or
polyvinyl pyrrolidone (PVP). Copovidone is a white or yellowish-white spray-
dried powder
that has a relatively fine particle size and good flow properties. It has a
typical slight odor .
and a faint taste in aqueous solutions. Because of the ratio of
vinylpyrrolidone to vinyl
acetate in copovidone, it is almost as universally soluble as polyvinyl
pyrrolidone. It
dissolves in extremely hydrophilic liquids such as water as well as in more
hydrophobic
solvents such as butanol. Copovidone has a molecular weight ranging from about
45000 to
about 70000 and is available commercially in different grades and trade names
such as
Kollidon VA 64.
It is contemplated within the scope of the invention that other binders such
as
polyvinyl pyrrolidone (PVP) with a molecular weight ranging from about 4000 to
about
1500000 and preferably about 30,000-1500000 can be used as a binder.
Polyvinylpyrrolidone is available in different grades based on K-value and
molecular weights
such as polyvinyl pyrrolidone with K value of 24-26, 29-32 or 85-95.
Preferably polyvinyl
pyrrolidone with K value 85-95 (Plasdone K-90/D , Kollidon 90F ) can be used
in the
present invention having high molecular weight (1,000,000-1,500,000) and
greater binding
capacity.
It is also contemplated that other binders can be used such as but not limited
to
hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxy ethyl
cellulose, polyvinyl
alcohol, sodium carboxy methyl cellulose, starches such as corn starch,
modified corn starch,
sugars, gum acacia and the like.
4
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
Metformin hydrochloride granules prepared with copovidone (copolyvidone,
Kollidon
VA 64) have been found to have a good compressibility. Metformin is
essentially granulated
with suitable binders, the binder concentration ranging from h about 0.1% to
about 10%
binder, preferably about 0.2% to about 5 % 2-4% binder and most preferably
about 0.25% to
about 4.5% binder. Although concentrations above 4% can give also give binding
effect,
there appears to be no substantial increase in binding. It is contemplated
within the scope of
the disclosure that multiple granulation steps can be preformed to improve
compressibility.
The solvent used with the binder for granulation is preferably water. It is
contemplated that other solvents such as isopropyl alcohol or the like can
also be employed.
Metformin granules so formed are uniformly dispersed in a controlled release
matrix
comprising of rate controlling polymers. In a further illustrative embodiment
according to
the disclosure Metformin granules so formed are uniformly dispersed in a
controlled release
matrix comprising of rate controlling polymers along with free metformin.
"Controlled-release" as used herein to describe a method and composition for
making
an active ingredient available to the biological system of a host. A
controlled release
preparation according to the present invention is one that achieves slow
release of a drug over
an extended period of time, thereby extending the duration of drug action over
that achieved
by conventional delivery. This admixture is typically compressed under
pressure to produce
a tablet. Drug is released from this tablet by diffusion and erosion. For
drugs of relatively
high solubility, the preferred polymeric matrices are those with a relatively
high molecular
weight. With such systems, release of the drug is achieved by allowing the
gastric fluid to
diffuse into the matrix where fluid dissolves the matrix-held drug and then
diffuses outward
while the matrix retains its integrity, or disintegrates at a rate that is
considerably slower than
the rate at which the drug is dissolved from matrix. Controlled release is
thus achieved by the
integrity of the matrix and the need for the gastric fluid to diffuse into the
matrix to reach the
drug.
In the present invention swelling and expanding system is employed. It is
contemplated within the scope of the invention that other compositions for
controlled or
extended release may be employed. The controlled release gastro-retentive
swelling system
of the present invention employs a combination of rate controlling polymers,
which swell
voluminously in presence of gastric contents to increase the dosage form size
such that it
precludes its passage through the pylorus. The term "rate-controlling polymer"
as used
herein includes hydrophilic polymers that are capable of retarding the release
of inetformin
5
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
hydrochloride in combination with other anti-diabetic agents in vivo when
metformin
hydrochloride and other anti-diabetic agents are dispersed in a polymeric
matrix formed from
the rate controlling polymers.
Preferred polymers for the controlled release system of high solubility drug
of the
present invention are those which ensure rapid hydration of the polymer matrix
to minimize
variable and undesirable burst of combination drugs, yet effectively control
the release of
drugs within a combination being liberated from the discrete particles or drug
granules. The
hydrophilic water-soluble polymers may be used individually or in combination.
Examples
of polymers suitable for this invention include the polymers well known in the
pharmaceutical art for their release retarding properties and may be selected
from the group
comprising acrylic polymers such as available as Eudragit RS, Eudragit RL,
natural gums as
xanthan gum, karaya gum, locust bean gum, guar gum, gelan gum, gum arabic,
tragacanth,
carrageenan, pectin, carboxymethyl cellulose (CMC) agar, alginic acid, sodium
alginate
polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethyl cellulose,
methyl
cellulose, vinyl acetate copolymers, polyethylene oxide, methacrylic acid
copolymers, maleic
anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof.
Preferred polymers with appropriate hydration characteristics include
hydroxypropylmethylcellulose 2208 USP (hydroxypropylmethylcellulose with a
methoxyl
content of 19-24% and a hydroxypropyl content of 7-12%), viscosity grades
ranging from
about 4000 to about 100,000cps and hydroxypropylmethylcellulose 2910 USP
(hydroxypropylmethylcellulose with a methoxyl content of 28-30% and a
hydroxypropyl
content of 7-12%), viscosity grades ranging from about 3 to about 150 cps.
Another
preferred polymer is sodium carboxy methylcellulose having viscosity of about
2000-50000
cps.
The amount of polymer relative to the drug may vary depending on the release
rate
desired, nature of the polymers and their physicochemical characteristics. The
amount of the
polymer in the dosage form generally varies from about 10% to about 50% by
weight of the
composition. Preferably, the amount of polymers varies from about 15% to about
45% by
weight of the dosage form. Most preferably, the amount of polymer is about 20%
to about
24% by weight of the dosage form. The polymer concentration can be reduced as
they are
utilized optimally due to their incorporation in dry form.
6
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
Additional excipients that are although not essential for the present
invention, are
required for the tableting process as known to those skilled in art, and may
be suitably
included.
The composition of the invention therefore typically includes pharmaceutically
acceptable excipients. As is well known to those skilled in the art,
pharmaceutical excipients
are routinely incorporated into solid dosage forms. This is done to ease the
manufacturing
process as well as to improve the performance of the dosage form. Common
excipients
include diluents, lubricants, granulating aids, colorants, flavorants,
surfactants, pH adjusters,
anti-adherents and gildants etc. Such excipients are routinely used in the
dosage forms of this
invention.
The present invention may additionally include one or more fillers or
excipients in an
amount within the range of from about 0 to about 90% by weight and preferably
from about I
to about 80% by weight such as lactose, sugar, corn starch, modified corn
starch, mannitol,
sorbitol, inorganic salts such as calcium carbonate and/or cellulose
derivatives such as wood
cellulose and microcrystalline cellulose.
As the composition is in the form of a tablet, it may include one or more
tableting
lubricants in an amount within the range of from about 0.2 to about 8% and
preferably from
about 0.5 to about 2% by weight of the composition, such as magnesium
stearate, stearic
acid, palmitic acid, calcium stearate, talc, polyethylene glycol, colloidal
silicon dioxide,
sodium stearyl fumarate, carnauba wax and the like and mixtures thereof. Other
conventional
pharmaceutical ingredients, which may optionally be present, include
preservatives,
stabilizers, and FD &C colors etc.
The composition made according to the present invention may be formulated as
tablets within a capsule or a tablet. Most preferably, the composition is a
tablet. The tablet
may optionally be coated with a thin layer of a film forming polymer or a
pharmaceutical
excipient. The controlled release preparation according to the invention may
conveniently be
film coated using any film coating material conventional in the pharmaceutical
art. It is
contemplated that the film coating can be formulated to delay the release of
any drug for a
selected period of time that is desirable for therapeutic reasons. Preferably
an aqueous film
coating is used.
The dosage form of present invention is a solid dosage form, preferably a
tablet,
which may vary in shape such as oval, triangle, almond, peanut, parallelogram,
pentagonal,
hexagonal, and trapezoidal. The preferred shapes are oval and parallelogram
forms.
7
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
A controlled release preparation according to the present invention is one
that
achieves slow release of a drug or drugs in combination over an extended
period of time,
thereby extending the duration of drug or drugs action over that achieved by
conventional
delivery. Preferably, such a preparation maintains a drug concentration in the
blood within
the therapeutic range for 12 hours or more.
Tablets formulated according to the invention allow for controlled release
metformin
hydrochloride in combination with other anti-diabetic agents over at least a
twelve-hour
period following oral administration.
Another preferred dissolution rate in vitro upon release of the controlled
release
preparation for administration twice daily according to the invention is
between 5 and 50%
(by weight) metformin hydrochloride and another anti-diabetic agent such as
glimepiride
released after 1 hour, between 10 and 75% (by weight) metformin hydrochloride
and another
anti-diabetic agent such as glimepiride released after 2 hours, between 20 and
95% (by
weight) metformin hydrochloride and another anti-diabetic agent such as
glimepiride released
after 4 hours, between 40 and 100% (by weight) metformin hydrochloride and
another anti-
diabetic agent such as glimepiride released after 8 hours, more than 50% (by
weight)
metformin hydrochloride and another anti-diabetic agent such as glimepiride
released after 12
hours, more than 70% (by weight) released after 18 hours and more than 80% (by
weight)
metformin hydrochloride and another anti-diabetic agent such as glimepiride
released after 24
hours. In one illustrative embodiment the glimepiride is released as follows:
1 hour greater
than about 10%; 4 hours greater than about 25%; 6 hours greater than about
40%; and 12
hours greater than 60%.
Tablets formulated according to the invention allow for controlled release
metformin
hydrochloride over at least a twelve-hour period following oral
administration, the in vitro
release rate preferably corresponds to the following % rate of metformin
hydrochloride
released as shown in Table 1:
TABLE I
TIME (H) % RELEASED
1 10-40
2 20-75
4 30-85
8
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
6 50-90
8 60-95
12 65-100
Yet another preferred preparation particularly suited for once-a-day dosing
has an in-
vitro release rate corresponding to the following % rate of metformin
hydrochloride released
as shown in Table 2:
TABLE 2
TIME (H) % RELEASED
1 00-50
2 30-75
4 40-85
6 50-100
8 60-100
12 65-100
A still farther preferred preparation in accordance with the invention is also
particularly suited for once-a-day dosing has an in vitro release rate
corresponding to the
following % rate of metformin hydrochloride released as shown in Table 3:
TABLE 3
TIME (H) % RELEASED
1 0-30
2 0-40
4 5-55
6 10-65
8 20-75
12 30-90
16 50-100
24 >80
9
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
Another preferred dissolution rate in vitro upon release of the controlled
release
preparation for administration twice daily according to the invention is
between 5 and 50%
(by weight) metformin hydrochloride released after 1 hour, between 10 and 75%
(by weight)
metformin hydrochloride released after 2 hours, between 20 and 95% (by weight)
metformin
hydrochloride released after 4 hours, between 40 and 100% (by weight)
metformin
hydrochloride released after 8 hours, more than 50% (by weight) metformin
hydrochloride
released after 12 hours, more than 70% (by weight) released after 18 hours and
more than
80% (by weight) metformin hydrochloride released after 24 hours.
A formulation in accordance with the invention suitable for once a day or
twice a day
dosing and may have a Tn,,_, of 3 to 10 hours, preferably 2 to 7 hours.
While the present invention has been described in terms of its specific
embodiments,
certain modifications and equivalents will be apparent to those skilled in the
art and are
intended to be included within the scope of the present invention. The details
of the
invention, its objects and advantages are explained hereunder in greater
detail in relation to
non-limiting exemplary illustrations.
The compounds of the invention may be administered alone or in combination
with
pharmaceutically acceptable carriers or excipients, in either single or
multiple doses. The
pharmaceutical compositions according to the invention may be formulated with
pharmaceutically acceptable carriers or diluents as well as any other known
adjuvants and
excipients in accordance with conventional techniques such as those disclosed
in Remington:
The Science and Practice of Pharmacy, 19'h Edition, Gennaro, Ed., Mack
Publishing Co.,
Easton, Pa.,1995.
The pharmaceutical compositions may be specifically forinulated for
administration
by any suitable route such as the oral, rectal, nasal, pulmonary, topical
(including buccal and
sublingual), transdermal, intracisternal, intraperitoneal, vaginal and
parenteral (including
subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route,
the oral route
being preferred. It will be appreciated that the preferred route will depend
on the general
condition and age of the subject to be treated, the nature of the condition to
be treated and the
active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms
such
as capsules, tablets, dragees, pills, lozenges, powders and granules. Where
appropriate, they
can be prepared with coatings such as enteric coatings or they can be
formulated so as to
provide controlled release of the active ingredient such as sustained or
prolonged release
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
according to methods well known in the art. I:iquid dosage forms for oral
administration
include solutions, emulsions, suspensions, syrups and elixirs. Pharmaceutical
compositions
for parenteral administration include sterile aqueous and non-aqueous
injectable solutions,
dispersions, suspensions or emulsions as well as sterile powders to be
reconstituted in sterile
injectable solutions or dispersions prior to use. Depot injectable
formulations are also
contemplated as being within the scope of the present invention. Other
suitable
administration forms include suppositories, sprays, ointments, cremes, gels,
inhalants, dermai
patches, implants etc. A typical oral dosage is in the range of from about
0.001 to about 100
mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body
weight per
day, and more preferred from about 0.05 to about 10 mg/kg body weight per day
administered in one or more dosages such as 1 to 3 dosages. The exact dosage
will depend
upon the frequency and mode of administration, the sex, age, weight and
general condition of
the subject treated, the nature and severity of the condition treated and any
concomitant
diseases to be treated and other factors evident to those skilled in the art.
The formulations
may conveniently be presented in unit dosage form by methods known to those
skilled in the
art. A typical unit dosage form for oral administration one or more times per
day such as I to
3 times per day may contain from 0.05 to about 3000 mg, preferably from about
0.1 to about
500 mg, and more preferred from about 0.5 mg to about 200 mg.
For parenteral routes such as intravenous, intrathecal, intramuscular and
similar
administration, typically doses are in the order of about half the dose
employed for oral
administration. The compounds of this invention are generally utilized as the
free substance
or as a pharmaceutically acceptable salt thereof. One example is a base
addition salt of a
compound having the utility of a free acid. When a compound of the formula (I)
contains a
free acid such salts are prepared in a conventional manner by treating a
solution or
suspension of a free acid of the formula (I) with a chemical equivalent of a
pharmaceutically
acceptable base. Representative examples are mentioned above. For parenteral
administration, solutions of the novel compounds of the formula (I) in sterile
aqueous
solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil
may be
employed. Such aqueous solutions should be suitably buffered if necessary and
the liquid
diluent first rendered isotonic with sufficient saline or glucose. The aqueous
solutions are
particularly suitable for intravenous, intramuscular, subcutaneous and
intraperitoneal
administration. The sterile aqueous media employed are all readily available
by standard
techniques known to those skilled in the art. Suitable pharmaceutical carriers
include inert
11
CA 02645318 2008-09-09
WO 2007/103563 PCT/US2007/006055
solid diluents or fillers, sterile aqueous solution and various organic
solvents. Examples of
solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine,
agar, pectin, acacia,
magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples
of liquid
carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty
acid amines,
polyoxyethylene and water. Similarly, the carrier or diluent may include any
sustained release
material known in the art, such as glyceryl monostearate or glyceryl
distearate, alone or
mixed with a wax. The pharmaceutical compositions formed by combining the
novel
compounds of the formula (I) and the pharmaceutically acceptable carriers are
then readily
administered in a variety of dosage forms suitable for the disclosed routes of
administration.
The formulations may conveniently be presented in unit dosage form by methods
known in
the art of pharmacy. Formulations of the present invention suitable for oral
administration
may be presented as discrete units such as capsules or tablets, each
containing a
predetermined amount of the active ingredient, and which may include a
suitable excipient.
Furthermore, the orally available formulations may be in the form of a powder
or granules, a
solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water
or water-in-oil
liquid emulsion. If a solid carrier is used for oral administration, the
preparation may be
tableted, placed in a hard gelatine capsule in powder or pellet form or it can
be in the form of
a troche or lozenge. The amount of solid carrier will vary widely but will
usually be from
about 25 mg to about I g. If a liquid carrier is used, the preparation may be
in the form of a
syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an
aqueous or non-
aqueous liquid suspension or solution. A typical tablet that may be prepared
by conventional
tableting techniques may contain:
12
