U.S. patent number 3,870,790 [Application Number 05/300,745] was granted by the patent office on 1975-03-11 for solid pharmaceutical formulations containing hydroxypropyl methyl cellulose.
This patent grant is currently assigned to Forest Laboratories, Inc.. Invention is credited to Hans Lowey, Herbert Henry Stafford.
United States Patent |
3,870,790 |
Lowey , et al. |
March 11, 1975 |
**Please see images for:
( Certificate of Correction ) ** |
SOLID PHARMACEUTICAL FORMULATIONS CONTAINING HYDROXYPROPYL METHYL
CELLULOSE
Abstract
A solid pharmaceutical composition in which the carrier consists
essentially of hydroxypropylmethylcellulose, or
hydroxypropylmethylcellulose admixed with up to about 20%
ethylcellulose, is prepared by compressing a mixture comprising one
therapeutic agent and the hydroxypropylmethylcellulose powder which
has been humidified to a moisture content of from about 5 to about
25% by weight at a low compression pressure. The solid
pharmaceutical composition obtained will release the active
ingredient contained therein evenly over a prolonged period, e.g.
from about 1 to 8 hours.
Inventors: |
Lowey; Hans (Mamaroneck,
NY), Stafford; Herbert Henry (Staten Island, NY) |
Assignee: |
Forest Laboratories, Inc. (New
York, NY)
|
Family
ID: |
26673978 |
Appl.
No.: |
05/300,745 |
Filed: |
October 25, 1972 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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5140 |
Jan 22, 1970 |
|
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626968 |
Mar 30, 1967 |
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Current U.S.
Class: |
424/469; 424/436;
514/777; 424/430; 424/480 |
Current CPC
Class: |
A61K
9/2054 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A61k 017/00 (); A61k 021/00 ();
A61k 027/00 () |
Field of
Search: |
;424/19,127,178,180,183,201,241,248,243,258,272,285,298,310,330,362 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Meyers; Albert T.
Assistant Examiner: Schenkman; Leonard
Parent Case Text
CROSS-REFERENCE
This is a continuation-in-part of U.S. application Ser. No. 5,140,
filed Jan. 22, 1970 now abandoned, which, in turn, is a
continuation-in-part of U.S. application Ser. No. 626,968, filed
Mar. 30, 1967, now abandoned.
Claims
What is claimed is:
1. A method of preparing a long-acting compressed buccal
composition for the administration of transmucosally absorbed
therapeutic agents consisting essentially of the therapeutic agent
and a carrier which comprises subjecting an effective amount of a
dry carrier consisting of from 80 to 100% of hydroxypropyl methyl
cellulose having a methoxyl content of 28 to 30% and a
hydroxypropyl content of 7 to 12% and from 20 to 0% of ethyl
cellulose having an ethoxy content of 48 to 49.5% to controlled
humidity for a time sufficient to establish a moisture content of
from about 5 to about 25%, mixing the moisturized carrier with a
therapeutically effective amount of the therapeutic agent and
compressing the mixture into solid shaped units at a pressure of
from about 5 to about 8 pounds per square inch.
2. The product prepared by the process of claim 1.
3. The product of claim 1 which additionally contains a synthetic
sweetening agent, a coloring agent, a flavoring agent and a
preservative.
Description
DETAILED DESCRIPTION
Sustained release products of conventional character are well known
to the art and have been found to have a number of advantages.
Specifically, the release of the medication contained therein is
uniform and continuous over a period of time, thereby avoiding the
necessity of frequent administration of the medicament while at the
same time achieving a desired blood level of active ingredient. The
preparation of sustained release compositions often requires a
rather substantial and complicated procedure and often the degree
of predictability and the release pattern are less than
optimum.
The use of cellulose derivatives such as
hydroxypropylmethylcellulose as an ingredient in pharmacetical
formulations is of course known. Thus U.S. Pat. No. 3,266,992
describes the incorporation of up to 30% of various cellulose
derivatives such as methylcellulose, sodium carboxymethylcellulose
and hydroxyethylcellulose, the particular derivative depending upon
the nature of the therapeutic agent, into tablets to effect rapid
disintegration thereof. U.S. Pat. No. 2,887,440 on the other hand
discloses the use of hydroxypropylmethylcellulose in enteric
coatings to prevent disintegration of the tablet core. It has also
been recognized that methylcellulose might itself be a desirable
material for certain pharmaceutical formulations but attempts at
achieving such products have not met with success. Thus U.S. Pat.
No. 2,949,401 recognizes the desirable properties of
methylcellulose in a buccal tablet containing vitamin A but limits
the amount to from 3 to 5%. Trotter and coworkers report several
unsuccessful attempts at directly compressing methylcellulose into
a troche and succeeded only by incorporating 25% superfine sugar
with the methylcellulose. Amer. Jour. Pharm, February 1956, pp.
50-56. The combination of cellulose derivatives with large amounts
of lactose is also described in U.S. Pat. No. 3,344,030. U.S. Pat.
No. 3,590,117 reports the unsatisfactory nature of
hydroxypropylmethylcellulose for troches. U.S. Pat. No. 3,312,594
describes troches containing carboxymethylcellulose but only in
combination with equal amounts of pectin and gelatin.
The present invention relates to a long-acting sustained dosage
unit, and the carriers and active ingredients in the composition
thereof, presented in a solid coherent form. The long-acting dosage
unit contains at least one active ingredient compressed with a
mixture containing a moisturized carrier consisting esentially of
100 to 80% by weight of hydroxypropylmethylcellulose and optionally
0 to 20% by weight of ethylcellulose. The carrier ingredient during
use gradually releases the active ingredient by contact with
fluids, such as saliva, gastric juices, and other natural
secretions and does so over an extended period, e.g., about 1 to 8
hours. In one aspect the invention comprises a long-acting troche,
lozenge or tablet. The solid pharmaceutical form according to the
present invention can however be utilized in other routes of
administration in addition to buccal. Thus the solid form may be
administered orally as a tablet to be swallowed or rectally or
vaginally as a suppository.
Specifically, the carrier is hydroxypropylmethylcellulose which has
been humidified under controlled conditions to a moisture content
of from about 5 to about 25% by weight. This material, optionally
containing ethylcellulose, can then be compressed at a low
pressure, e.g. only 5 to 8 pounds per square inch, which, because
of the moisture content, is sufficient to shape the material into a
solid coherent pharmaceutical form such as a troche to be sucked or
used in the oral cavity so as to effect a gradual release of the
active therapeutic ingredient which is absorbed through the oral
mucosa through the blood stream. Higher degrees of compression,
e.g., up to about 30 pounds per square inch, yield a harder and
more long lasting composition as might be desired for example in a
suppository to be inserted in the rectum or vagina, or a tablet to
be simply swallowed.
According to the present invention it has now been found that a
reliable and effective long acting sustained action solid dosage
unit can be very simply made by compressing an appropriate amount
of practically any desired active ingredient or medicament with a
pre-moisturized hydroxypropylmethylcellulose powder or with a
mixture of a combination of moisturized
hydroxypropylmethylcellulose and ethylcellulose powder. The release
time, the dosage unit and pattern of release can be controlled by
the relative amounts of hydroxypropylmethylcellulose and
ethylcellulose employed, the size and weight of the tablet product,
the degree of compression or a combination thereof, bearing in mind
that a high degree of moisturization permits the use of low
compression pressures, and visa versa, for the blend of active
ingredient and cellulose powder and that increased compression
increases the composition's span of action. It is thus an important
feature of the present invention that a sustained release product
can be readily and easily prepared containing, as the sole carrier,
varying amounts of hydroxypropylmethylcellulose and ethylcellulose
having a predetermined moisture content and that by controlled
variation of the moisture content of the alkylated cellulose
carrier powder, the duration of the release period of the active
medicament held in the compacted tablet may be controlled. The
release of the active ingredient is, therefore, controlled by the
size and the weight, moisture content and degree of compression
pressure exercised on the lozenge, suppository or tablet at the
time it is being formed from the pre-wetted powder and active
medicament.
In general, the long acting carrier products of the present
invention are produced by combining the appropriate amount of
active ingredient into the shape of troches, lozenges, tablets or
suppositories with a mixture of from about 100-80% by weight of
hydroxypropylmethylcellulose and from about 0-20% by weight of
ethylcellulose. The product can also contain adjuvants such as a
synthetic sweetening agent as for example saccharin, a nontoxic
food grade color such as FD&C Yellow No. 10, a flavoring agent
such as cherry flavor and a preservative such as p-methylbenzoic
acid. The only criterion for the addition of such materials is that
they do not tend to dehydrate the product before or after it is
tableted by compression techniques.
Specific techniques for the manufacture and use of the long acting
carrier will be set forth in greater detail below but an
illustration of the improved activity of the product may briefly be
noted by the following illustration. For example, a 5 grain lozenge
when held in the mouth will release its active ingredient in a
regular manner over a period of one and one-and-one-half hours by
dissolution or disintegration of the lozenge by the saliva fluids.
If the same lozenge is inserted in the upper cavity of the mouth,
the release then can be extended to 3 hours. Moreover a shaped
product or tablet of the present invention which has a weight of
about 10 grains is noted to take almost twice as long to release
its active ingredient as a 5 grain product.
When used as a lozenge, release through the action of the saliva is
continuous and the active ingredient then passes through the
gastro-intestinal tract into the blood stream. However, when the
composition is positioned in the buccal pouch, absorption of the
active ingredient takes place through the mucosa membrane lining
the pouch directly through the capillaries in the blood stream.
A similar pattern can be observed when the solid pharamaceutical
form takes the form of a suppository. Here again the exclusive
carrier has highly desirable properties in that it is
non-irritating, substantially neutral and adherent.
While the solid pharmaceutical forms of the present invention
intended for oral administration; i.e., tablets to be swallowed,
will be subjected to the effects of both gastric and intestinal
fluids and mechanical wear within the gastrointestinal tract, a
prolonged rate of release is also seen here.
The invention has flexibility and versatility dependent upon the
particular nature of the active ingredient which is to be
dispensed, the treatment or condition for which the active
ingredient is indicated, the route of administration and the
desired length of release time of the active ingredient. It has
been found that one may for example prepare a 50 lb. mixture for
the production of long acting troches from a composition indicated
in the following Table:
TABLE ______________________________________ No. Make of Materials
Lbs. Ozs. Grs. ______________________________________ 1 0.10%
Calcium Cyclamate 350 2 1.00% Cherry Flavor 8 3 0.10% Methyl
Paraben 350 4 0.01% Propyl Paraben 35 5 0.50% Lake Dye Red No. 2 4
6 Mixture of 85% Methocel HG 60 49 2 140 (20% of H.sub.2 O),
premium viscosity 50 and 15% Ethyl- cellulose N50
______________________________________
With respect to the foregoing Table, it is to be understood that
the calcium cyclamate ingredient can be replaced by sodium
cyclamate or other suitable food grade, nontoxic synthetic
sweetening agent such as saccharin. A different flavoring material
obviously can be substituted for the cherry flavor and other
approved colors can be used in place of the Lake Dye Red No. 2. It
is further to be understood that the invention is not limited to
the preferred use of 85% by weight hydroxypropylmethylcellulose and
15% by weight of ethylcellulose because variations in the relative
proportions are not only permissible but are intended as these
variations affect the release time and pattern of the active
ingredient.
In preparing troches from the above mixture, items 1, 2, 3 and 4
are weighed out and thoroughly mixed. Item 5, which is the food
grade dye, is placed in a mortar and rubbed with some of the
mixture of Items 1, 2, 3 and 4 following which the remainder of
Items 1, 2, 3 and 4 is added and the rubbing is conducted until a
homogenous blend is obtained. Item 6, which is the specified
cellulose powder mixture, is added to the previously produced
mixtures of Items 1, 2, 3, 4 and 5 and the entire composition is
blended until uniformity is achieved. The uniform dry mixture of
ingredients is then spread out on trays and thoroughly sprayed with
a 35% mixture of ethanol and distilled water. The thus treated
mixture is allowed to dry overnight and is then ground on a
Fitzpatrick mill to an average 20-40 mesh particle size. The powder
derived from the Fitzpatrick mill is next placed on trays which
trays are put into a steam room and held there overnight under
conditions of very high humidity for the express purpose of
creating in the previously dry blend, certain moisture levels which
are important in the ultimate performance of each tablet in
simultaneously maintaining its integrity and sustained even release
of active ingredient. As a means of maintaining the desired
humidity at a fixed level in the powder, trays filled with water
are placed in the steam room to maintain the even consistency of
the humidity level to insure adequate wetting of the powder. The
room temperature is about 75.degree.F and humidity is maintained
between about 78 to 82% for 24 hours (overnight). The resulting
material will have a moisture content from about 20 to about 25% by
weight.
After a constant moisture level is thus achieved, the active
ingredient is added and the entire batch of material is placed in
the hopper of a conventional tableting machine which is set up with
half-inch punches and dies and the machine is adjusted and
regulated for 8 pounds of pressure per square inch and for product
size. In this manner, 71/2 grain or 10 grain tablets preferably,
are produced and by following the same procedure, but suitably
further adjusting the machine, 12 grain or other size tablets are
produced.
Alternatively, the procedure is carried out by introducing the
hydroxypropylmethylcellulose or a mixture of the
hydroxypropylmethylcellulose with ethylcellulose into an oven
chamber having an exhaust aperture which is at that time in closed
or shut position. The chamber is provided with a heating unit and a
forced air blower, which is inoperative at this stage of the
procedure, the heat and forced air being applied at a subsequent
stage. The material to be processed is placed in thin layers (not
more than 1/4 inch thick) on trays of the oven chamber which are
lined with heat-resistant parchment paper and the trays are placed
on racks in the oven chamber using only alternate shelves, thereby
providing a predetermined amount of spacing between the layers of
material being treated. There is then placed within the oven
chamber a humidifier equipped with a humidistat which is pre-set to
maintain humidity in the oven chamber at 85 - 90%, the humidifier
being filled with sufficient distilled or deionized water to last
for 24 to 36 hours. The humidifier is now activated and the oven
chamber is closed and the process is allowed to proceed under the
85 -90% humidity for a minimum of 24 hours. Humidification can be
continued for up to 36 hours or even longer if desired, although
there is no special advantage in exceeding 36 hours and unduly
extended times are apt to be uneconomical, but the treatment should
be continued at least about 24 hours. The humidifier is then
removed from the oven chamber, the exhaust aperture opened by
manipulation of the valve and the forced air blower is activated
thereby applying heat at a controlled temperature in the range of
100.degree. to 120.degree.F (43.degree. to 49.degree.C). The
moisture content will then decrease, depending upon the length of
time the material is treated with the hot air. At the end of 12
hours for example the moisture content of the treated material is
at its lowest limit of the range, about 5%. This is not an exact
limit since this added moisture content can be as low as 4 or 41/2
%, as determined by a standard moisture determination apparatus.
The 12-hour period just referred to is also approximate as the
duration of the period may vary somewhat above or below 12 hours,
but it has been found in practice that the period should not exceed
approximately 12 hours.
When the required added moisture content is achieved, the treated
material is removed from the oven and passed through a No. 2
stainless steel screen employing a Fitzpatrick mill and processed
as described above.
Variations in the two extremes are of course readily apparent, the
critical factor being that the hydroxypropylmethylcellulose is so
treated that its moisture content is stabilized at a higher level
than is normally encountered.
The hydroxypropylmethylcellulose preferably employed is identified
as Methocel HG 60 which is a commercial methylcellulose product
manufactured by the Dow Chemical Company, Midland, Michigan and has
a methoxyl percentage of 28 to 30%, a hydroxypropoxyl percentage of
7 to 12%, is soluble in water and organic solvents, has a normal
gel temperature of 60.degree.F and demonstrates an average
viscosity of 50 centipoises (range 40 to 60, 2% aqueous
solution).
As regards the ethylcellulose, this material corresponds to that
defined in the National Formulary XIII with a standard ethoxy
content ranging between 44.0 and 51.0%, preferably 48-49.5%, by
weight. The preferred material corresponds to ethylcellulose N50,
the number N50 indicating the viscosity in centipoises of a 5% by
weight solution of the product in a 80/20 toluene/ethanol solvent
at a temperature of 25.degree.C. These viscosity numbers are
indicative of the size of the ethylcellulose molecules, the larger
the molecule, the greater the viscosity and can be further referred
to in the standard charts on the products which are readily
available.
The active ingredient may be of any suitable nature such as
insulin, vitamins, hormones, analgesics, local anesthetics,
epinephrine, antiinflammatory steroids, progestational agents,
antibiotics, antiseptics, antimycotics, antacids and the like. The
nature of the therapeutic agent is not critical and any drug, or
stable combination of drugs, can be incorporated into these novel
pharmaceutical forms. This is particularly important since some
active medicaments such as insulin, antidiuretic hormones and
epinephrine become inactivated when incorporated into conventional
or previously known sustained release products where the products
are swallowed and the release occurs in the gastric fluids or in
the intestinal fluids or in a combination of both. Some active
agents such as ACTH, epinephrine, vitamin B.sub.12, iron insulin,
antidiuretic hormones, prednisolone and nitroglycerine as well as
antiobesity agents and antacids can, in accordance with the present
invention, be administered via the transmucosal absorption route.
However those therapuetic agents which are active when swallowed,
can also be administered in the new pharmaceutical carrier of the
present invention, the composition being used exactly like a
conventional tablet. Similarly, antimicrobial agents such as
furazolidone and nifuroxime can be administered in a vaginal
suppository. Products of the present invention are also useful as
demulcents in the treatment of painful ulcerations, inflammations,
and irritations. These effects have been shown by in vitro and in
vivo clinical tests.
Moreover, it can be shown by X-ray studies a tablet prepared
according to the present invention for very long release, while
gradually dissolving remains coherent for most of its passage
through the gastro-intestinal tract. Hence a tablet of the
moisturized hydroxypropylmethylcellulose and barium sulfate (as an
X-ray contrast agent) having a total weight of 600 mg, a diameter
of 12.7 mm, a thickness of 3.15 mm and a hardness of 6.6
lbs/in.sup.2 can still be seen in X-rays for more than 5 hours
after administration. A typical progression is as follows: 1 hr.
small intestine 1 hr. 35 min. do. 2 hr. 20 min. do. 5 hr. 10 min.
caecum
Since the therapeutic agent is being continuously released, the
observed period of activity will be even longer than this.
The invention is further illustrated by the following
non-limitative examples:
EXAMPLES 1-11
SUSTAINED RELEASE TROCHE FORMULATIONS
50 LB. MIXTURE FOR 50,000 TABLETS AT 7 GRAINS
EXAMPLE 1 ______________________________________ PREDNISOLONE, 4
MG. No. Make of Materials Lbs. Ozs. Grs.
______________________________________ 1. Prednisolone 7 60 2.
0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10%
Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red
No. 2 4 7. Methocel HG 60 48 11 80 hydroxypropylmethylcellulose,
premium, viscosity 50, moisture 20% by weight
______________________________________
EXAMPLE 2 ______________________________________ EPINEPHRINE, 1 MG
No. Make of Materials Lbs. Ozs. Grs.
______________________________________ 1. Epinephrine 1 330 2.
0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10%
Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red
No. 2 4 7. Methocel HG 60 49 245 hydroxypropylmethylcellulose,
premium,viscosity 50 moisture 20% by weight
______________________________________
EXAMPLE 3 ______________________________________ DIBUCAINE, 3 MG
No. Make of Materials Lbs. Ozs. Grs.
______________________________________ 1. Dibucaine 5 150 2. 0.10%
Calcium cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl
Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2
4 7. Methocel HG 60 48 12 440 hydroxypropylmethylcellulose
premium,viscosity 50 moisture 20% by weight
______________________________________
EXAMPLE 4 ______________________________________ BENZOCAINE, 20 MG
No. Make of Materials Lbs. Ozs. Grs.
______________________________________ 1. Benzocaine 2 3 300 2.
0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10%
Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red
No. 2 4 7. Methocel HG 60 46 14 290 hydroxypropylmethylcellulose
premium, viscosity 50 moisture 20% by weight
______________________________________
EXAMPLE 5 ______________________________________ TRIAMCINOLONE
ACETONIDE, 0.25 MG No. Make of Materials Lbs. Ozs. Grs
______________________________________ 1. Triamcinolone Acetonide
188 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4.
0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake
Dye Red No. 2 4 7. Methocel HG 60 49 1 402
hydroxypropylmethylcellulose premium, viscosity 50 moisture 20% by
weight ______________________________________
EXAMPLE 6 ______________________________________ HEPARIN, 50 MG No.
Make of Materials Lbs. Ozs. Grs.
______________________________________ 1. Heparin 5 8 165 2. 0.10%
Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl
Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2
4 7. Methocel HG 60 35 5 210 hydroxypropylmethylcellulose premium,
viscosity 50, moisture 20% by weight 8. Ethocel N50 ethylcellulose
9 2 70 ______________________________________
EXAMPLE 7 ______________________________________ VITAMIN B.sub.12,
1000 MCG No. Make of Materials Lbs. Ozs. Grs.
______________________________________ 1. Vitamin B.sub.12 1 330 2.
0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10%
Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red
No. 2 4 7. Methocel HG 60 41 10 195 hydroxypropylmethylcelluose
premium, viscosity 50 moisture 20% by weight 8. Ethocel N50
ethylcellulose 8 3 345 ______________________________________
EXAMPLE 8 ______________________________________ INSULIN, 250 INT.
UNITS No. Make of Materials Lbs. Ozs. Grs.
______________________________________ 1. Insulin 1 330 2. 0.10%
Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl
Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2
4 7. Methocel HG 60 hydroxypropylmethylcellulose, premium,
viscosity 50 moisture 20% by weight
______________________________________
EXAMPLE 9 ______________________________________ SODIUM
BICARBONATE, 0.3 GM -- GRAIN TABLETS No. Make of Materials Lbs.
Ozs. Grs. ______________________________________ 1. Sodium
Bicarbonate 33 1 23 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry
Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6.
0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 53
hydroxypropylmethylcellulose premium, viscosity 50 moisture 20% by
weight 8. Ethocel N50 ethylcellulose 13 14 412
______________________________________
EXAMPLE 10 ______________________________________ d-DESOXYEPHEDRINE
HYDROCHLORIDE, 5 MG No. Make of Materials Lbs. Ozs. Grs.
______________________________________ 1. d-Desoxyephedrine
Hydrochloride 8 390 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry
Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6.
0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 49 7 45
hydroxypropylmethylcellulose, premium, viscosity 50 moisture 20% by
weight ______________________________________
In examples 1 - 10, the calcium cyclamate can be replaced by 0.1
the amount of sodium saccharin while the Lake Dye Red No. 2 can be
replaced by another pharmaceutically acceptable coloring agent or
omitted altogether from the formulation.
EXAMPLE 11
REPRESENTATIVE RELEASE PATTERNS
260 individual tests have been made on 31 subjects with both
lozenges and tablets inserted either in the buccal pouch on held
sublingually, and show the following results: LOZENGES
______________________________________ 1) Partial dissolution
Medium range per 1/10 gram time. carrier, 15.8 to 21.5 minutes. 2)
Total dissolution Medium range per 7 grain time. lozenge, 81 to 108
minutes. 3) Total dissolution Medium range per 14 grain time.
tablet, 158 to 215 minutes. ______________________________________
TABLETS INSERTED IN BUCCAL POUCH OR USED SUBLINGUALLY
______________________________________ 1) Partial dissolution
Medium range per 1/10 gram time. carrier, 29.4 to 42.1 minutes. 2)
Total dissolution Medium range per 7 grain time. tablet, 149 to 212
minutes. 3) Total dissolution Medium range per 14 grain time.
tablet, 294 to 421 minutes.
______________________________________
EXAMPLE 12 ______________________________________ Analgesic Tablet
Ingredients mg/tablet ______________________________________ 1
Aspirin powder U.S.P. 525.0 2 Methocel HG 60
hydroxypropylmethylcellulose, premium, viscosity 50, moisture 5% by
weight 325.5 3. Glycine 45.0 4. Syloid 244 micron size silica 4.5
______________________________________
Ingredients 1, 2 and 3 are mixed in a bowl into which ingredient 4
is added after screening and the whole blended for 20 minutes and
compressed in a tableting machine having a one-half inch die size
and a one-half inch punch to make tablets with an average weight of
0.9 g and a thickness of 0.210 .+-. 0.01 inch. The hardness of the
tablet was 22-28.6 lbs/square inch.
EXAMPLE 13 ______________________________________ Antihistamine
Tablet Ingredients mg/tablet ______________________________________
1 Chlorpheniramine maleate U.S.P. 12.60 2 Methocel HG 60 509.20
hydroxypropylmethylcellulose, premium, viscosity 50, moisture 41/2%
by weight 3 Methyl paraben U.S.P 0.52 4 Propyl paraben U.S.P. 0.06
5 Syloid 244 micron size silica 2.63
______________________________________
Ingredient 2 was placed in a container and ingredients 1, 3, 4 and
5 were weighed out and added after screening and the whole blended
for 20 minutes. The compression into tablets was conducted on a
tableting machine using a die size of seven-sixteenths inch with a
pound of seven-sixteenths inch to obtain a tablet thickness of
0.250 .+-. 0.01 inch with a tablet hardness of 22-28.6 lbs/square
inch. Each tablet weighed 0.525 g.
EXAMPLE 14 ______________________________________ Laxative Tablet
Ingredients mg/tablet ______________________________________ 1
Phenolphthalein U.S.P. 33.0 2 Methocel HG 60 513.64
hydroxypropylmethylcellulose, premium, viscosity 50, moisture 5% by
weight 3 Methyl paraben U.S.P. 0.55 4 Propyl paraben U.S.P. 0.06 5
Syloid 244 2.75 ______________________________________
Ingredients 1 and 2 were placed in a stainless steel vessel to
which, after screening, were added ingredients 3, 4 and 5 and the
whole blended for 20 minutes and compressed as in Example 13. The
tablet thickness was 0.250 .+-. 0.01 inch and the hardness was 22.2
lbs/square inch. Each tablet weighed 0.55 g.
EXAMPLE 15 ______________________________________ Laxative Tablet
Ingredients mg/tablet ______________________________________ 1
Phenolphthalein U.S.P. 66.0 2 Methocel HG 60 480.64
hydroxypropylmethylcellulose, premium, viscosity 50, moisture 4% by
weight 3 Methyl paraben U.S.P. 0.55 4 Propyl paraben U.S.P. 0.06 5
Syloid 244 2.75 ______________________________________
The same procedure was followed as in Example 13 with the same
results.
EXAMPLE 16 ______________________________________ Vitamin Tablet
Ingredients mg/tablet ______________________________________ 1
Ascorbic acid, U.S.P., powder 105 2 Methocel HG 60 691
hydroxypropylmethylcellulose, premium, viscosity 50, moisture 5% by
weight 3 Syloid 244 4 ______________________________________
Ingredients 1 and 2 were weighed out as in the preceding examples
and placed into a stainless steel bowl into which ingredient 3 was
added after screening and the whole blended for 20 minutes and
compressed as previously described. The tablets had a thickness of
0.210 .+-. 0.01 inch and a hardness of 22.2-28.6 lbs/square inch.
Each tablet weighed 0.8 g.
EXAMPLE 17 ______________________________________ Ingredients
Amount/Suppository ______________________________________ 1
Furazolidone 0.005 g 2 Nifuroxime 0.007 g 3 Methocel HG 60 1.988 g
hydroxypropylmethylcellulose, premium, viscosity 50, moisture 7.5%
by weight ______________________________________
The ingredients are thoroughly mixed and compressed in a similar
fashion to that described above utilizing however a suppository
mold to yield a vaginal suppository weighing 2 g.
EXAMPLE 18 ______________________________________ Ingredients
Amount/Suppository ______________________________________ 1
Prednisolone 5.25 mg 2 Methocel HG 60 1131.90 mg
hydroxypropylmethylcellulose premium, viscosity 50, moisture 7.5%
by weight 3 Syloid 244 2.85 mg
______________________________________
The above ingredients are mixed and thoroughly blended for 30
minutes and then compressed to form rectal suppositories of 1.14 g
each.
* * * * *