Note: Descriptions are shown in the official language in which they were submitted.
WO 95/19759
PCTIUS95/01018
1
PROCESS FOR SOLUBILIZING DIFFICULTLY SOLUBLE
PHARMACEUTICAL ACTIVES
TECHNICAL FIELD
The present invention relates to a process for enhancing the solubility of
difficultly
1o soluble pharmaceutical actives in a mixture of polyethylene glycol,
polyvinylpyrrolidone,
and propylene glycol.
BACKGROUND OF THE INVENTION
Liquid, and especially concentrated liquid pharmaceutical compositions offer
several advantages over solid compositions. Liquids are easy to swallow and
provide an
excellent vehicle for the uniform delivery of pharmaceutical actives.
Moreover, liquids
provide a rapid onset of pharmacologic action, since the composition does not
first have to
disintegrate and dissolve in the gastrointestinal tract. Likewise,
concentrated liquid
compositions offer certain distinct advantages. These compositions are ideally
suited for
incorporation into easy-to-swallow soft, flexible capsules. Encapsulation of
this nature
2o permits the accurate and uniform delivery of unit dose amounts of a
pharmaceutical active,
encompassing even those instances where relatively small amounts of a
pharmaceutical
active are to be delivered. In addition, soft gelatin capsules are
aesthetically appealing
(especially when filled with a transparent liquid) and can be manufactured in
a wide variety
of sizes, shapes, and colors.
These advantages notwithstanding, it is often difl:<cult to prepare such com-
positions using the desired pharmaceutical active however. Many pharmaceutical
actives
are poorly soluble and, therefore, require relatively large volumes of solvent
for
dissolution, resulting in impractically large doses. Also, encapsulating such
large volumes
into easy-to-swallow gelatin capsules presents obvious difficulties,
suggesting the
3o immediate importance of concentrated liquid compositions. Furthermore, the
situation
becomes even more complicated when multiple pharmaceutical actives are
involved, and
. particularly where the difficultly soluble pharmaceutical active is in
combination with a
water soluble pharmaceutical active(s).
The current approach to this solubility problem is to force solubility into
small
volumes of solvent by means of a step-wise process incorporating heat. This
step-wise
process consists of dissolving the diflicultly soluble pharmaceutical active
in polyethylene
2181241
2
glycol with heat, followed by the addition of any additional pharmaceutical
actives. As a
separate admixture, polyvinylpyrrolidone is dissolved in a solution of water
and propylene
glycol. Finally, the polyvinylpyrrolidone solution is then added to the
original batch
solution to complete the process. Because the resultant concentrated liquid
(or fill) is a
supersaturated solution of the difficultly soluble pharmaceutical active, it
is even more
difficult to increase the resultant composition's concentration of the
difficultly soluble
active.
The present inventor has discovered that by using a polyvinylpyrrolidone with
a
specific viscosity average molecular weight of from about 5,000 to about
25,000 provides
to dissolution of significantly higher levels of the difficultly soluble
pharmaceutical active.
1t is, therefore, an object of the present invention to describe a process
which
provides for increased solubility of difficultly soluble pharmaceutical
actives. A further
object of the present invention is to enhance stability of the resultant
composition by
reducing the tendency of the difficultly soluble pharmaceutical active to
precipitate out of
solution. These and other-objects of this invention will become apparent in
light of the
following discussion.
C OF TIC rrrtnrr
The present invention relates to a process for enhancing the solubility of
diffcultly soluble
pharmaceutical actives by combining and mixing in the presence of heat until
dissolved from about
1% to about 40% by weight of at least one diflycultly soluble pharmaceutical
active in a solution
comprising:
i) from about 20~/° to about 70% by wieght of a polyethylene glycol;
ii) from about 4% to about 20% by weight of a polyvinylpyrrolidone having
a viscosity average molecular weight from about 5,000 to about 25,000; and
iii) from about 1 % to about 10% by weight of a propylene glycol.
The process preferably further comprises combining and mixing until dissolved
the above
solution with a separate admixture of from about 0.5% to about 20% bf at least
one
additional pharmaceutical active in from about l% to about 50% of an aqueous
phase.
All percentages and ratios used herein are by weight and all measurements are
at
30 25°C, unless otherwise indicated.
DETAILED DESCRIPTION OF THE INVENTION
The term "difftcuttly soluble pharmaceutical active", as used herein,
describes an
active having a solubility of less than or equal to 1% by weight in water at
25°C. This
term is defined to also include the descriptive terms "sparingly soluble";
"slightly soluble";
35 "very slightly soluble"; "practically insoluble, or insoluble"; and their
equivalents as defined
B
2181241
3
in the USP XXII, p.8 (1990).
Concentrated Liauid Pharmaceutical Compositions
The highly concentrated liquid pharmaceutical compositions of the present
invention comprise the following essential, as well as optional, components.
Polyethylene Glycol
An essential component of the present compositions is a polyethylene glycol.
Polyethylene glycols generally are clear, viscous liquids or white solids
which are
soluble in water and many organic solvents. These polymers correspond to the
general
formula:
H(OCHZCHZ)nOH
where n is greater than or equal to 4. Polyethylene glycols are described in
G.M.
Powell, III in Handbook of Water-Soluble Gums & Resins, R.L. Davidson, Ed.
(McGraw-Hill, New York, 1980) pp. 18/1-18/31. Polyethylene glycols, which are
also
known as "PEGS" or "polyoxyethylenes", are designated by both their average
molecular
weight range and their average "n" value as in the above designated formula.
For
example, polyethylene glycol 400, which is also known by the CTFA designation,
PEG-
8, has an average molecular weight range from 380-420 and an average value of
n
between 8.2 and 9.1. See CFTA Cosmetic In;~redient Dictionary, Third Edition
(1982),
pp. 201-203; and The Merck Index. Tenth Edition, entry 7441, p. 1092 (1983).
Polyethylene glycols useful herein are mixtures of those which are liquids at
room temperature or having a melting point slightly thereabove. Preferred
mixtures
include those polyethylene glycols having a molecular weight range of from
about 300
to about 1000 and corresponding n values of from about 6 to about 20. More
preferred
are those of polyethylene glycols having a molecular weight range of from
about 400
to about 1000 and corresponding n values of from about 8 to about 20. Most
preferred
are those of pblyethylene glycols having a molecular weight range of from
about 600
to about 1000 and corresponding n values of from about 12 to about 20. Liquid
and
low-melting polyethylene glycols are commercially available from Union Carbide
(Danbury, CT) under the Carbowax~ trademark. See "Carbowax~ Polyethylene
Glycols", Union Carbide Technical Bulletin f 4772M-ICD 11/86-20M.
Polyethylene glycols having an average molecular weight below about 300 are
B
2181241
4
not desirable for use in the instant invention since such polyethylene glycols
tend to
diffuse into, plasticize, and ultimately disrupt the soft gelatin shells which
can be
employed to encapsulate the compositions described herein.
T'he process for preparing the highly concentrated liquid compositions of the
present invention comprises adding from about 20% to about 70% polyethylene
glycol,
more preferably from about 30 % to about 60%, and most preferably from about
35
to about 55%.
Polvvin~pvrrolidone
An essential component of the present compositions is polyvinylpyrrolidone
("PVP"), which is a polymei of N-vinyl-2-pyrrolidone having the following
formula:
,s ~°
7
cH Ct~
L-
Polyvinylpyrrolidones are described in.Lc Blecher et al: in Handbook of Water-
Soluble Gums & Resins, R.L. Davidson, Ed. (McGraw-Hill, New York, 1980)pp.
21/1-
21/21. Polyvinylpyrrolidone has different solubility characteristics based on
its
polymeric structure. Long-chain polyvinylpyrrolidone, which is also known as
povidone, has good solubility in water and a number of organic solvents. Cross-
linked
polyvinylpyrrolidone, which is also known as crospovidone, is insoluble in
virtually all
common solvents. Both the soluble and insoluble forms of polyvinylpyrrolidone
are
commercially available from GAF Chemicals Company (Wayne, NJ) under the
Plasdone~ and Polyplasdone~ trademarks, respectively, and from BASF
Aktiengesellschaft (Ludwigshafen, Germany) under the Kollidon~ trademark.
Soluble
forms ofpolyvinylpyrrolidone include Plasdone~ K-25, Plasdone~ K-26/28,
Plasdone~
K-29/32, Plasdone~ C-15, Plasdone~ C-30, Plasdone~ C-90, Kollidon~ 12 PF,
Kollidon ~17 PF, Kollidon~ 25, Kollidon~ 30, and Kollidon~ 90. Insoluble forms
2181241
of polyvinylpyrrolidone include Polyplasdone XL~, Polyplasdone XL~10,
Kollidon~CL, and Kollidon~ CL-M. See "Tableting With Plasdone~", GAF Technical
Bulletin 2302-11081 (1986); "Polyplasdone XL~, Polyplasdone XL~ 10", GAF
Technical Bulletin 2302-099 R2 (1984); and "Kollidon~ Grades,
Polyvinylpyrrolidone
5 for the Pharmaceutical Industry", BASF Technical Bulletin MEF 129e, Register
2, May
1986 (Bn).
The soluble forms of polyvinylpyrrolidone are preferred for use in the present
invention. Preferred are soluble polyvinylpyrrolidones having a viscosity
average
molecular weight in the range from about 5000 to about 25,000; more preferred
are
those having a viscosity average molecular weight in the range from about 5000
to
about 15,000; and most preferred are those having a viscosity average
molecular weight
from about 5,000 to about 10,000. Moreover, mixtures of two or more soluble
polyvinylpyrrolidones of different average molecular weight can be employed.
The process for preparing the highly concentrated liquid compositions of the
instant invention comprises adding from about 1% to about 28% of a soluble
polyvinylpyrrolidone, more preferable from about 1% to about 15%, and most
preferably from about 2% to about 10%.
Preferably, the ratio of the total amount of polyethylene glycol to
polyvinylpyrrolidone should be at least about 2.5:1.
Propylene Glycol
Propylene glycol, which is represented by the formula:
CH3CHOHCHzOH
is well known in the art for its solvent and/or humectant properties. A
colorless and
viscous liquid, propylene glycol is miscible with water, alcohols and many
organic
solvents. Propylene glycol is described in Hawley's Condensed Chemical
Dictionary
pp. 970-971, (Revised by Richard J. Lewis, Sr.) (12th ed. 1993). Propylene
glycol
suitable for use in the present invention is obtainable from any number of
suppliers,
Dow Chemical being one.
Difficultly Soluble Pharmaceutical Actives
The compositions of the instant invention contain at least one difficultly
soluble
pharmaceutical active as an essential component. In general, these activities
have a
solubility less than or equal to about 1 percent by weight in water at
25°C. Useful
classes of pharmaceutically-active compounds which can be incorporated into
the
present compositions include analgesics, anti-inflammatory agents, anti-
pyretics, calcium
B
2181241
6
channel blockers, beta-blockers, antibacterials, antidepressants.
antidiabetics, anti-
emetics, antihistamines, cerebral stimulants, sedatives, anti-parasitics,
expectorants,
diuretics, decongestants, antitussives, muscle relaxants, anti-Parkinsonian
agents,
broncholdilators, cardiotonics, antibiotics, antivirals, nutritional
supplements (such as
vitamins, minerals, fatty acids, amino acids, and the like), and mixtures
thereof.
Difficultly soluble pharmaceutical actives selected from the non-narcotic
analgesic/nonsteroidal anti-inflammatory drugs are especially useful in the
present
invention. Examples such as drugs are disclosed in U.S. Patent No. 4,522,828,
to
Sunshine et al., issued June 1 l, 1985.
Examples of preferred difficultly soluble pharmaceutical actives in the
present
invention include, but are not limited to, acetaminophen, acetylsalicylic
acid, ibuprofen,
fenbuprofen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, naproxen,
their
pharmaceutically-acceptable salts, and mixtures thereof. Acetaminophen is
especially
preferred for use in the present invention.
The process for preparing the highly concentrated liquid compositions of the
instant invention comprises adding from about 1 % to about 40% of a
difficultly soluble
pharmaceutical active, more preferably from about 15% to about 35%, and most
preferably from about 25% to about 35%.
Additional Pharmaceutical Actives
The compositions of the instant invention can optionally contain one or more
additional pharmaceutical actives having a solubility greater that the
difficultly soluble
pharmaceutical actives described above. In general, these actives have a
solubility
greater than about 1 percent by weight in water at 25°C. Such
additional
pharmaceutical actives may also be selected from among the pharmaceutical
categories
previously mentioned.
Specific examples of additional pharmaceutical actives useful in the present
invention include, but are not limited to, pseudoephedrine and its salts such
as
pseudoephedrine hydrochloride; dextromethorphan and its salts such as
dextromethorphan hydrobromide; doxylamine and its salts such as doxylamine
succinate;
phenindamine and its salts such as phenindamine hydrogen tartrate; pheniramine
and its
salts such as pheniramine maleate; chlorpheniramine and its salts such as
chlorpheniramine maleate; ephedrine and its salts such as ephedrine sulfate;
triprolidine
and its salts such as triprolidine hydrochloride; diphenhydramine and its
salts such as
diphenhydramine hydrochloride, diphenhydramine citrate, and diphenhydramine
s
2181241
7
8-chlorotheophyllinate;phenyltoxylamine
anditssalts;guaifenesin;phenylpropanolamine
hydrochloride; and mixtures thereof. Preferred additional pharmaceutical
actives are
dextromethorphan hydrobromide, doxylamine succinate,
pseudoephedrinehydrochloride,
chlorpheniramine maleate, guaifenesin, triprolidine hydrochloride,
diphenhydramine
hydrochloride and mixtures thereof.
A further class of optional actives include those useful in promoting or
maintaining healthy skin. Examples of such actives are disclosed in U.S.
Patent
5,073.371. to Turner et al. issued December 17, 1991.
The process for preparing the highly concentrated liquid compositions of the
instant invention comprises adding one or more of these optionally additional
pharmaceutical actives at a concentration of from about 0.5% to about 20%.
Coolants
In addition, the present invention may optionally incorporate a cooling agent
or
a combination or cooling agents. Suitable cooling agents are those described
in U.S.
Patent 4,136.163, January 23, 1979, to Watson et al., U.S. Patent 4.230,668,
October
28, 1980, to Rowsell et al. and U.S. Patent 4,032,661, to Rowsell et al. A
particularly
preferred cooling agent is N-ethyl-p-menthane-3-carboxamide (WS-3 supplied by
Sterling Organics), taught by the above noted U.S. Patent 4.136.163. Another
particularly preferred cooling agent is 3-1-menthoxypropane 1,2-diol (TK-10
supplied
by Takasago Perfumery Co., Ltd., Tokyo, Japan). This material is described in
detail
in U.S. Patent 4,459,425, July 10, 1984 to Amano et al.
Other Optional Comaonents
Optional components which can be incorporated into the compositions of the
instant invention include coolants, colorings, flavourings, preservatives,
lubricants, flow-
enhancers, filling aids, anti-oxidants, essences, and other aesthetically
pleasing
components.
Process for Solubilizing Difficultly Soluble Pharmaceutical Actives
The highly concentrated liquid pharmaceutical compositions are prepared using
art-recognized principles and methodologies in mixing the ingredients together
and in
choosing the type of mixing equipment to be used. In a preferred manner of
execution,
the difficultly soluble pharmaceutical active, polyethylene glycol, propylene
glycol and
polyvinylpyrrolidone, are combined in the presence of heat and mixed until
dissolved
to form a homogeneous solution. Upon dissolution ofthe difficultly soluble
pharmaceu-
tical active, additional pharmaceutical actives may then be added to this
batch solution
or
s
WO 95119759
1 ~ 1 _?_ 41 PCT/US95/01018
8
dissolved separately in an aqueous phase. The process is completed once all
additional
pharmaceutical actives have been added, whether by direct addition to the
original batch
solution and/or by indirectly transferring the separately formed admixture to
the original
batch.
Soft Gelatin Capsules
2181241
9
Preselected amounts of the highly concentrated liquid pharmaceutical
compositions of the present invention can also be encapsulated in a soft
gelatin shell.
Optionally, the soft gelatin shell is essentially transparent so as to enhance
the aesthetic
qualities of the capsule. The soft gelatin shells comprise the following
essentail, as well
as optional, components.
Gelatin
Gelatin is an essential component of the soft gelatin shells of the instant
invention. The starting material used in the manufacture of soft capsules is
obtained
by the partial hydrolysis of collagenous material, such as the skin, white
connective
tissues, or bones of animals. Gelatin material can be classified as Type A
gelatin,
which is obtained from the acid-processing of porcine skins and exhibits an
isoelectric
point between pH 7 and pH 9; and Type B gelatin, which is obtained from the
alkaline-
processing of bone and animal (bovine) skins and exhibits an isoelectric point
between
pH 4.7 and pH 5.2. Blends of Type A and Type B gelatins can be used to obtain
a
gelatin with the requisite viscosity and bloom strength characteristics for
capsule
manufacture. Gelatin suitable for capsule manufacture is commercially
available fmm
the Sigma Chemical Company, St. Louis, Mo. For a general description of
gelatin and
gelatin-based capsules, see Reminetons' Pharmaceutical Sciences, 16th ed.,
Mack
Publishing Company, Easton, Pa. (1980), page 1245 and pages 1576-1582; and
U.S.
Patent 4,935,243, to Borkan et al., issued June 19, 1990.
The soft gelatin shell of the capsules of the instant invention, as initially
prepared, comprises from about 20% to about 60% gelatin, more preferably from
about
25% to about SO% gelatin, and most preferably from about 40% to about 50%
gelatin.
The gelatin can be of Type A, Type B, or a mixture thereof with bloom numbers
ranging from about 60 to about 300.
Plasticizes
A plasticizes is another essential component of the soft gelatin shells of the
instant invention. One or more plasticizers is incorporate~d~to produce soft
gelatin shell.
The soft gelatin thus obtained has the required flexibility characteristics
for use as a
encapsulation agent. Useful plasicizers of the present invention include
glycerin,
sorbitan, sorbitol, or similar low molecular weight polyols, and mixtures
thereof.
The shell of the present invention, as initially prepared, comprises from
about
10% to about 35% plasticizes, preferably from about 10% to about 25%
plasticizes, and
most preferably from about 10% to about 20% plasticizes. A preferred
plasticizes
useful in the present invention is glycerin.
z~ ~»4~
WO 95/19759 PCTIUS95/01018
l!3
Water
The soft gelatin shells of the instant invention also comprise water as an
essential
component. Without being limited by theory, the water is believed to aid in
the rapid
dissolution or rupture of the soft gelatin shell upon contact with the
gastrointestinal fluids
encountered in the body.
The shell of the present invention, as initially prepared, comprises from
about I S%
to about 50% water, more preferably from about 25% to about 40% water, and
most
1o preferably from about 30% to about 40% water.
Other Optional Components
Other optional components which can be incorporated into the soft gelatin
shells in-
clude colorings, flavorings, preservatives, anti-oxidants, essences, and other
aesthetically
pleasing components.
Soft Gelatin Shell Preparation and Encapsulation
The solubilized pharmaceutical compositions of the present invention can be en-
capsulated within any conventional soft gelatin shell that is capable of
substantially
containing the composition for a reasonable period of time. The soft gelatin
shells of the
instant invention can be prepared by combining appropriate amounts of gelatin,
water,
2o plasticizer, and any optional components in a suitable vessel and agitating
and/or stirring
while heating to about 65°C until a uniform solution is obtained. This
soft gelatin shell
preparation can then be used for encapsulating the desired quantity of the
solubilized fill
composition employing standard encapsulation methodology to produce one-piece,
hermetically-sealed, soft gelatin capsules. The gelatin capsules are formed
into the desired
shape and size so that they can be readily swallowed. The soft gelatin
capsules of the
instant invention are of a suitable size for easy swallowing and typically
contain from
about 100 mg to about 2000 mg of the solubilized pharmaceutical active
composition.
Soft gelatin capsules and encapsulation methods are described in P.K.
Wilkinson et al.,
"Softgels: Manufacturing Considerations", Drubs and the Pharmaceutical
Sciences. 41
(Specialized Drua Delivery Systems), P. Tyle, Ed. (Marcel Dekker, Inc., New
York,
1990) pp.409-449; F.S. Hom et al., "Capsules, Soft", Encyclopedia of
Pharmaceutical
Technoloav, vol. 2, J. Swarbrick and J.C. Boylan, eds. (Marcel Dekker, Inc.,
New York,
1990) pp. 269-284; M.S.. Pate) et al., "Advances in Softgel Formulation
Technology",
Manufacturing Chemist, vol. 60, no. 7, pp. 26-28 (July 1989); M.S. Pate) et
al., "Softgel
Technology", Manufacturins Chemist, vol. 60, no. 8, pp. 47-49 (August 1989);
R.F.
218124 1
II
Jimerson, "Softgel (Soft Gelatin Capsule) Update", Drug Development and
Industrial
Pharmac (~rphex '86 Conference), vol. 12, no. 8 & 9, pp. 1133-I 144 (1986);
and
W.R. Ebert, "Soft Elastic Gelatin Capsules: A Unique Dosage Form",
Pharmaceutical
Technolosv, vol. 1, no. 5, pp 44-50 (1977). Methods for tempering soft gelatin
capsules are described in U.S. Patent 5,200,191 to Steele et al. The resulting
soft
gelatin capsule is soluble in water and in gatrointestinal fluids. Upon
swallowing the
capsule, the gelatin shell rapidly dissolves or ruptures in the
gastrointestinal tract
thereby introducing the pharmaceutical actives into the physiological system.
EXAMPLES
The following examples further describe and demonstrate embodiments within
the scope of the present invention. The examples are given solely for the
purpose of
illustration and are not to be construed as limitations of the present
invention, as many
variations thereof are possible without departing from the spirit and scope of
the
invention.
EXAMPLE 1
Solubilized Pharmaceutical Composition
A highly concentrated solution containing acetaminophen in combination with
other pharmaceutical actives is prepared from the following ingredients:
Ingredients Wei hght%
Acetaminophen 31.25
Pseudoephedrine HCI 2.88
Dextromethorphan HBr 1.44
Doxylamine Succinate 0.60
Polyethylene Glycol 600 24.38
Polyethylene Glycol 1000 22.14
Propylene Glycol 4.33
Polyvinylpyrollidone ' 8.17
Water Purified 4.81
' Available as Kollidon K-17 PF from BASF Chem. Co. (Viscosity average
molecular
weight ~ 10,000)
A solution of the polyethylene glycols, propylene glycol, and polyvinylpyrroli-
done is prepared by mixing and warming these compositions to 70°C.
Acetaminophen
is then dissolved into this solution, stirring and heating the solution to
120°C in the
presence of
21 ~ 1 ?_ 41 pCT~S95101018
WO 95!19759
a-
nitrogen. Once the acetaminophen is dissolved
the solution is removed from the heat.
In
a separate container, pseudoephedrine an HBr and doxylamine
HC1, dextromethorph
succinate are dissolved in water at room
temperature by stirring. Finally, this
separate
admixture is combined with the original
batch solution and mixed until uniform.
Examples II-III are further examples of
concentrated solutions containing
acetaminophen in combination with other tives and are manufactured
pharmaceutical ac in
a manner substantially similar to Example
I
EXAMPLE II
Solubilized Pharmaceutical Composition
to Ingredients Weieht
Acetaminophen 31.25
Pseudoephedrine HC1 2.88
Dextromethorphan HBr 1.44
Doxylamine Succinate 0.60
Polyethylene Glycol 600 24.38
Polyethylene Glycol 1000 22.14
Propylene Glycol 4.33
Polyvinylpyrollidonel 8.17
Water Purified 4.81
!Available as Kollidon K-12 PF from BASF (Viscosity average
Chem.Co. molecular
weight ~ 5,000)
EXAMPLE III
Solubilized Pharmaceutical Composition
Ingredients Weight
Acetaminophen 31.25
Pseudoephedrine HCl 2.88
Dextromethorphan HBr I .44
Chlorpheniramine Maleate 0.19
Polyethylene Glycol 600 24.52
3o Polyethylene Glycol 1000 22.40
Propylene Glycol 4.33
Polyvinylpyrollidone 1 8.17
Water Purified 4.82
l Available as Kollidon K-17 PF from BASF(Viscosity average
Chem.Co. molecular
weight ~ 10,000)
?_181241
WO 95119759 PCT/US95I01018
l3
EXAMPLE IV
Solubilized Pharmaceutical Composition
A highly concentrated solution containing acetaminophen and guaifenesin in
combination with other pharmaceutical actives is prepared from the following
ingredients:
Ingredients Weight
Acetaminophen 31.25
Pseudoephedrine HCI 2.88
Dextromethorphan HBr 0.96
Guaifenesin 9.62
to Polyethylene Glycol 600 21.12
Polyethylene Glycol 1000 19.26
Propylene Glycol 2.88
Polyvinylpyrollidone 1 8.17
Water Purified 3.86
1 Available as Kollidon K-17 PF from BASF Chem.Co. (Viscosity average
molecular
weight ~ 10,000)
A solution of polyethylene glycols, propylene glycol, and polyvinylpyrrolidone
is
prepared by mixing and warming to 70°C. Acetaminophen is then dissolved
into this
solution, stirring and heating the solution to 120°C in the presence of
nitrogen. Once the
2o acetaminophen is dissolved and the solution removed from heat, the
guaifenesin is next
added and dissolved. In a separate container, pseudoephedrine HCI,
dextromethorphan
HBr and doxylamine succinate are dissolved in water at room temperature by
stirring.
Finally, this separate admixture is combined with the original batch solution
and mixed
until uniform.
EXAMPLE V
Solubilized Pharmaceutical Composition
Example V is a further example of a concentrated solution containing aceta-
minophen and guaifenesin in combination with other pharmaceutical actives and
is
manufactured in a manner substantially similar to Example IV.
- 3o tneredients Weight
Acetaminophen 31.35
Pseudoephedrine HCI 2.88
Dextromethorphan HBr 0.96
Guaifenesin 9.62
Polyethylene Glycol 600 21.12
WO 95!19759 PCT/US95101018
21$1241
~a
Polyethylene Glycol 1000 19.26
Propylene Glycol 2.88
Polyvinylpyrollidone 1 8.17
Water Purified 3.86
!Available as Kollidon K-12 PF from BASF Chem.Co. (Viscosity average molecular
weight ~ 5,000)
EXAMPLE VI
Solubilized Pharmaceutical Composition
A highly concentrated solution containing acetaminophen is prepared from the
to following ingredients
I redients Weight
Acetaminophen 31.25
Polyethylene Glycol 600 26.96
Polyethylene Glycol 1000 24.48
Propylene Glycol 4.33
Polyvinylpyrrolidone 1 8.17
Water Purified 4.&l
I Available as Kollidon K-30 from BASF Chem.Co. (Viscosity average molecular
weight
38,000)
2o A solution of the polyethylene glycols, propylene glycol, and
polyvinyipyrrolidone
is prepared by mixing and warming these components to 70°C.
Acetaminophen is then
dissolved into this solution, stirring and heating the solution to
120°C in the presence of
nitrogen gas. Once the acetaminophen is dissolved, the solution is removed
from the heat.
Finally, a measured quantity of the aqueous phase is combined with the
original batch
solution and mixed until uniform.
EXAMPLE VII
Solubilized Pharmaceutical Composition
A highly concentrated solution containing acetaminophen and pseudoephedrine
HCl is prepared from the following ingredients
3o Ineredients Weight
Acetaminophen 31.25
Pseudoephedrine HCl 2.88
Polyethylene Glycol 600 . 25.45
Polyethylene Glycol 1000 23.1 1
Propylene Glycol 4.33
WO 95!19759 21 ~ 12 41 pCT~S95/01018
l~
Polyvinylpyrrolidone 1 8. I 7
Water Purified 4.81
1 Available as Kollidon K-30 from BASF Chem.Co. (Viscosity average molecular
weight
38,000)
A solution of the polyethylene glycols, propylene glycol, and
polyvinylpyrrolidone
is prepared by mixing and warming these components to 70°C.
Acetaminophen is then
dissolved into this solution, stirring and heating the solution to
120°C in the presence of
nitrogen gas. Once the acetaminophen is dissolved, the solution is removed
from the heat.
In a separate container, pseudoephedrine HCl is dissolved in water at room
temperature
to by stirring. Finally, this separate admixture is combined with the orivinal
batch solution
and mixed until uniform.
EXAMPLE VIII
Softeel Capsule Containing a Solub'~I'zed Pharmaceutical Composition
A soft gelatin capsule is first prepared form the~following ingredients:
Insredients Wei h~ t
Gelatin 47.00
Glycerin l 5.00
Water Purified qs 100
The above ingredients are combined in a suitable vessel and heated with mixing
at
2o about 65°C to form a uniform solution. Using standard encapsulation
methodology, the
resulting solution is used to prepare soft gelatin capsules containing
approximately 1040
mg. of the compositions of Examples I-VII. The resulting soft gelatin capsules
are
suitable for oral administration.
l.-,,
.~ .
