U.S. patent application number 11/593760 was filed with the patent office on 2007-03-08 for process for co-spray drying liquid herbal extracts with dry silicified mcc.
Invention is credited to Wilheim Barkulin, David Schaible, Bob Sherwood, Karl-Hans Theissing, Joseph A. Zeleznik.
Application Number | 20070053978 11/593760 |
Document ID | / |
Family ID | 29255274 |
Filed Date | 2007-03-08 |
United States Patent
Application |
20070053978 |
Kind Code |
A1 |
Sherwood; Bob ; et
al. |
March 8, 2007 |
Process for co-spray drying liquid herbal extracts with dry
silicified MCC
Abstract
A process for preparing dry extracts from a liquid extract and
at least one additional substance by a spray-drying process,
characterized in that said at least one additional substance is
added to the spray-drying process in a dry form during the
spray-drying processes.
Inventors: |
Sherwood; Bob; (Amenia,
NY) ; Zeleznik; Joseph A.; (Poughkeepsie, NY)
; Schaible; David; (Ulster Park, NY) ; Barkulin;
Wilheim; (Alsbach, DE) ; Theissing; Karl-Hans;
(Alzenau-Horstein, DE) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Family ID: |
29255274 |
Appl. No.: |
11/593760 |
Filed: |
November 7, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10256855 |
Sep 27, 2002 |
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11593760 |
Nov 7, 2006 |
|
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60334443 |
Nov 30, 2001 |
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60334398 |
Nov 29, 2001 |
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Current U.S.
Class: |
424/464 ;
424/725 |
Current CPC
Class: |
A61K 9/1652 20130101;
A61K 9/1611 20130101; A61K 9/19 20130101 |
Class at
Publication: |
424/464 ;
424/725 |
International
Class: |
A61K 36/18 20070101
A61K036/18; A61K 9/20 20060101 A61K009/20 |
Claims
1. A process for preparing dry extracts from a liquid extract and
at least one additional substance by a spray-drying process,
characterized in that said at least one additional substance is
added to the spray-drying process in a dry form during the
spray-drying processes.
2. The process according to claim 1, characterized in that said
liquid extract is the extract of a medicinal plant.
3. The process according to claim 1, characterized in that said at
least one additional substance is a galenic auxiliary agent.
4. The process according to claim 3, characterized in that said
auxiliary agent is selected from the group consisting of lactose,
maltodextrin, dextrin, dry glucose, starch, microcrystalline
cellulose, Povidone.RTM., polyethylene glycol, calcium phosphate,
magnesium stearate, precipitated silicic acid, precipitated silica,
highly dispersed silica, sorbitol, mannitol, and mixtures
thereof.
5. The process according to claim 1, characterized in that the
particle size of said at least one additional substance is within a
range of from 1 to 500 .mu.m.
6. A process of creating agglomerated particles containing an
herbal extract comprising combining a wetted herbal extract with
dry silicified microcrystalline cellulose using a spray dryer to
form agglomerated particles.
7. The process of claim 6, wherein the herbal extract is
hygroscopic.
8. A process of creating agglomerated particles containing an
herbal extract comprising: a) providing an herbal extract suitable
for spray drying; and b) combining the herbal extract with dry
silicified microcrystalline cellulose in a dryer to form
agglomerated particles.
9. The process of claim 8, wherein the herbal extract is
hygroscopic.
10. The process of claim 8, wherein the silicified microcrystalline
cellulose is formed into a slurry before spray drying.
11. The process of claim 8, wherein the silicified microcrystalline
cellulose is combined with the active agent prior to spray
drying.
12. The process of claim 1, wherein the auxiliary agent is
silicified microcrystalline cellulose.
13. A method of manufacturing agglomerated particles containing a
herbal extract comprising combining a wetted herbal extract with
dry silicified microcrystalline cellulose in a dryer to form
agglomerated particles.
14. The method of claim 13, wherein said dryer is a spray
dryer.
15. The method of claim 13, wherein said silicified
microcrystalline cellulose comprises excipient particles comprising
a particulate agglomerate of microcrystalline cellulose coprocessed
with from about 0.1% to about 20% by weight silicon dioxide, the
microcrystalline cellulose and silicon dioxide being in intimate
association with each other and said silicon dioxide being
integrated with or partially coating said microcrystalline
cellulose, said silicon dioxide portion of said agglomerate being
derived from a silicon dioxide having an average primary particle
size from about 1 nm to about 100 .mu.m.
16. The method of claim 13, wherein said silicon dioxide is derived
from a silicon dioxide having an average primary particle size from
about 5 nm to about 40 .mu.m.
17. The method of claim 13, wherein said silicon dioxide is derived
from colloidal silicon dioxide.
18. The method of claim 13, wherein said silicon dioxide is from
about 0.5% to about 10% by weight, based on the weight of said
microcrystalline cellulose.
19. The method of claim 13, wherein said excipient particles have
an average particle size of from about 10 .mu.m to about 500
.mu.m.
20. The method of claim 13, wherein said silicon dioxide is derived
from a silicon dioxide having a surface area from about 175
m.sup.2/g to about 350 m.sup.2/g.
21. The method of claim 19, wherein said excipient has a bulk
density from about 0.35 g/ml to about 0.55 g/ml.
22. The process of claim 6, wherein the herbal extract is selected
from the group consisting of Alfalfa Leaf, Alfalfa Juice,
Aloee-emodin, Andrographolide, Angelica Root, Astragalus Root,
Bilberry, Black Cohosh Root, Black Walnut Leaf, Blue Cohosh Root,
Burdock Root, Cascara Bark, Cats Claw Bark, Catnip Leaf, Cayenne,
Chamomile Flowers, Chaste Tree Berries, Chickweed, Chinese Red Sage
Root, Cranberry, Chrysophanol, Comfrey Leaf, Cramp Bark, Damiana
Leaf, Dandelion Root CO, Devil's Claw Root, Diosgenin, Dong Quai
Root, Dong Quai; Echinacea, Echinacea Angustifolia Root, Echinacea
Purpurea Herb Root and Echinacea Angust./Purpurea Blend CO,
Echinacea Angust./Goldenseal Blend, Eleuthero (Siberian) Ginseng
Root, Emodin, Eyebright Herb, Fenugreek, Feverfew Herb CO, Of-Ti
Root, Of-Ti, Garcinia Cambogia, Gentian Root, Ginger, Ginko Biloba
Ginger Root, Ginseng, Ginko Leaf, Ginseng Root, Goldenseal Root,
Gotu Kola Herb, Grape Seed, Grape Skin, Green Tea, Green Tea,
Decaf, Guarana Seeds, Gynostemma Pentaphyllum, Hawthorn Berries,
Hawthorn Leaf, Hesperdin, Hops Flowers, Horehound Herb, Horse
Chestnut, Horsetail, Hyssop Leaf, Huperzine A, Juniper Berries,
Kava Kava Root, Kola Nut, Lavender Flowers, Lemon Balm, Licorice
Root, Lobelia Herb, Lomatium, Marshmallow Root, Milk Thistle Seed,
Milk Thistle, Mullein Leaf, Myrrh, Naringin, Neohesperidin, Nettle
Leaf, Olive Leaf, Oregon Grape Root, Papain, Parsley Leaf &
Root, Passion Flower, Pau D'Arco Bark, Pennyroyal, Peppermint Leaf,
Physcion, Polystictus Versicolor Mushroom, Quercetin, Red Clover
Blossoms, Red Clover, Red Raspberry Leaf, Red Yeast Rice, Reishi
Mushrooms, Rhein, Rhubarb Root, Rosemary Leaf, Rutin, Sarsaparilla
Root, Saw Palmetto, Saw Palmetto Berry, Schisandra Berries,
Schisandra, Scullcap Herb, Shavegrass Herb, Sheep Sorrel, Shepard's
Purse Herb, Shitake Mushroom, Slippery Elm Bark, Sown Orange,
Soybean, Stevia Rebaudiana, St. John's Wort, Tetrandrine, Turmeric,
Usnea Lichen, Uva Ursi, Uva Ursi Leaf, Valerian Root, White Willow
Bark, Wild Yam Root, Yellow Dock Root, Yohimbe Bark, Yucca Root,
and combinations thereof.
Description
[0001] This application claims priority from U.S. Provisional
Application Ser. Nos. 60/334,443 and 60/334,398, filed Nov. 30,
2001 and Nov. 29, 2001, respectively, the entire disclosures of
which are hereby incorporated by reference.
BACKGROUND
[0002] Spray dryers are well known in the art for drying
pharmaceutical and nutriceutical active agents and excipients. In
general, a spray dryer is used to process fluid materials into
powders. Typically, the fluid material is introduced into the spray
dryer in the form of a solution, suspension, emulsion, slurry, or
thin paste. In operation, the fluid material is fed from a feed
delivery system to an atomizer. The atomizer disperses the fluid
material into the drying chamber in fine droplets. A heated air
supply applies heated air to the fine droplets in the drying
chamber, causing the fine droplets to be dried into a powder, the
powder being collected in a collection system. Spray dryers are
widely used in the preparation of active agents. For example, it is
known to spray dry an active agent in the form of a fluid material
(for example, a liquid herbal extract) to form a powder, and
thereafter, to blend the powder with conventional tableting agents,
and then compress the resulting mixture into a tablet.
[0003] Examples of such tableting agents include lubricants,
diluents, binders, disintegrants, and direct compression vehicles.
Lubricants are typically added to avoid the material(s) being
tableted from sticking to the punches. Commonly used lubricants
include magnesium stearate, stearic acid, sodium stearyl fumarate,
hydrogenated vegatable oil, and calcium stearate. Such lubricants
are commonly included in the final tableted product in amounts of
less than 1% by weight. Diluents are frequently added in order to
increase the bulk weight of the material to be tableted in order to
make the tablet a practical size for compression. This is often
necessary where the dose of the drug is relatively small. Binders
are agents which impart cohesive qualities to the powdered
material(s). Commonly used binders include starch, and sugars such
as sucrose, glucose, dextrose, and lactose. Typical disintegrants
include starch derivatives and salts of carboxymethylcellulose.
Direct compression vehicles include, for example, processed forms
of cellulose, sugars, and dicalcium phosphate dihydrate, among
others. Microcrystalline cellulose is an example of a processed
cellulose that has been utilized extensively in the pharmaceutical
industry as a direct compression vehicle for solid dosage
forms.
[0004] Silicified microcrystalline cellulose is a particularly
useful direct compression vehicle. Silicified microcrystalline
cellulose is a particulate agglomerate of coprocessed
microcrystalline cellulose and from about 0.1% to about 20% silicon
dioxide, by weight of the microcrystalline cellulose, the
microcrystalline cellulose and silicon dioxide being in intimate
association with each other, and the silicon dioxide portion of the
agglomerate being derived from a silicon dioxide having a particle
size from about 1 nanometer (nm) to about 100 microns (.mu.m),
based on average primary particle size. Preferably, the silicon
dioxide comprises from about 0.5% to about 10% of the silicified
microcrystalline cellulose, and most preferably from about 1.25% to
about 5% by weight relative to the microcrystalline cellulose.
Moreover, the silicon dioxide preferably has a particle size from
about 5 nm to about 40 .mu.m, and most preferably from about 5 nm
to about 50 .mu.m. Moreover, the silicon dioxide preferably has a
surface area from about 10 m.sup.2 g to about 500 m.sup.2/g,
preferably from about 50 m.sup.2/g to about 500 m.sup.2/g, and more
preferably from about 175 m.sup.2/g to about 350 m.sup.2/g.
Silicified microcrystalline cellulose, and methods for its
manufacture, are described in U.S. Pat. No. 5,585,115, the entire
disclosure of which is hereby incorporated by reference. Silicified
microcrystalline cellulose is commercially available from Penwest
Pharmaceuticals, Inc., under the trademark Prosolv.RTM.. Prosolv is
available in a number of grades, including, for example, Prosolv
SMCC 50, Prosolv SMCC 90, and Prosolv HD.
SUMMARY OF THE INVENTION
[0005] In accordance with one embodiment of the present invention,
a solid dosage form is provided which includes an active agent and
silicified microcrystalline cellulose, the dosage form being formed
by a) combining a wetted active agent with dry silicified
microcrystalline cellulose in a dryer to form agglomerated
particles; and b) incorporating the agglomerated particles into the
solid dosage form. In certain preferred embodiments, step. b)
comprises co-drying said silicified microcrystalline cellulose,
said active agent, and colloidal silicon dioxide in a dryer.
Preferably, the dryer is a spray dryer, and, in certain
embodiments, the active agent may be an herbal extract.
[0006] In accordance with another embodiment of the present
invention, a solid dosage form is provided which includes an active
agent and silicified microcrystalline cellulose, the dosage form
being formed by a) providing an active agent suitable for spray
drying; b) combining the active agent and silicified
microcrystalline cellulose in a spray dryer to form agglomerated
particles; and c) incorporating the agglomerated particles into a
solid dosage form. In accordance with further aspects of this
embodiment, the silicified microcrystalline cellulose may be in a
slurry, suspension, solution,.or emulsion (with or without the
active agent) prior to being combined with the active agent in the
dryer. Alternatively, the silicified microcrystalline cellulose may
be introduced into the dryer in dry form
[0007] In accordance with another embodiment of the present
invention, a method of manufacturing a tablet containing an herbal
extract is provided which comprises: a) providing an extract
composition comprising an herbal extract suitable for spray drying;
b) combining the herbal extract with a dry silicified
microcrystalline cellulose in a dryer to form agglomerated
particles; and c) compressing the agglomerated particles into
tablets.
[0008] In accordance with another embodiment of the present
invention, an oral solid dosage form is provided which comprises at
least about 60% ginseng extract and from about 25 to about 40%
silicified microcrystalline cellulose. In accordance with another
embodiment of the present invention, a tablet is provided which
comprises at least about 60% St John's Wort extract and from about
25 to about 40% silicified microcrystalline cellulose. In
accordance with another embodiment of the present invention, a
tablet is provided which comprises at least about 60% artichoke
leaves extract and from about 25 to about 40% silicified
microcrystalline cellulose.
[0009] In accordance with yet another embodiment of the present
invention, agglomerated particles of an active agent and silicified
microcrystalline cellulose are provided, the agglomerated particles
being formed by combining the active agent and dry silicified
microcrystalline cellulose in a dryer to form agglomerated
particles, the agglomerated particles having an average particle
size of from about 10 .mu.m to about 500 .mu.m. Preferably, the
agglomerated particles having an average particle size of from
about 15 .mu.m to about 300 .mu.m.
[0010] In accordance with still another embodiment of the present
invention, a tablet is provided that comprises an herbal extract
and augmented microcrystalline cellulose prepared by spray drying a
wetted herbal extract with dry agglomerated particles comprised of
microcrystalline cellulose and a compressibility augmenting agent
selected from the group consisting of pharmaceutically acceptable
colloidal metal oxides and colloidal carbon black. In certain
embodiments, the colloidal metal oxide may be colloidal titanium
dioxide.
[0011] In accordance with another embodiment of the present
invention, a process for preparing dry extracts from a liquid
extract and at least one additional substance by a spray-drying
process is characterized in that said at least one additional
substance is added to the spray-drying process in a dry form during
the spray-drying processes.
[0012] As described in further detail below, the agglomerated
particles in accordance with certain embodiments of the present
invention described above provide a number of advantages including
superior flow characteristics and superior compaction
characteristics to prior art compositions. As one of ordinary skill
in the art will appreciate, the superior compaction characteristics
provided by these embodiments of the present invention allow faster
and more efficient processing for tablets, and, moreover, allow a
larger percentage of active agent to be included in each
tablet.
[0013] The term "environmental fluid" is meant for purposes of the
invention to encompass, e.g., an aqueous solution, or
gastrointestinal fluid.
[0014] By "sustained release" it is meant for purposes of the
invention that a therapeutically active medicament is released from
the formulation at a controlled rate such that therapeutically
beneficial blood levels (but below toxic levels) of the medicament
are maintained over an extended period of time, e.g., providing a
12 hour or a 24 hour dosage form.
[0015] By "primary particle size" it is meant for purposes of the
invention that the particles are not agglomerated. Agglomeration is
common with respect to silicon dioxide particles, resulting in a
comparatively average large agglomerated particle size.
[0016] By fluid (or liquid ) material, it is meant for purposes of
the invention that the material (e.g., the active agent) is
sufficiently wetted to be suitable for subsequent spray drying.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is a block diagram of a spray dryer including a fluid
active agent and a source of silicified microcrystalline
cellulose.
[0018] FIG. 2 is a graph of volume flow (ml/s) as a function of
aperture size (mm) for the St. John's Wort compositions of Examples
3 and D.
[0019] FIG. 3 is a graph of volume flow (ml/s) as a function of
aperture size (mm) for the St. John's Wort compositions of Examples
6, 7, and E.
[0020] FIG. 4 is a graph of moisture uptake for the St. John's wort
compositions of Examples 4 and D.
[0021] FIG. 5 is a graph of tablet hardness as a function of
compaction force for the compositions of Examples 7 and E.
[0022] FIG. 6 is a graph of tablet hardness as a function of
compaction force for the compositions of Examples 8, 9-1, and
F.
[0023] FIG. 7 is a graph of tablet hardness as a function of
compaction force for the compositions of Examples 9-2, 12, 13, 14,
and H.
[0024] FIG. 8 is a graph of moisture uptake for the Ginseng extract
compositions of Examples 2 and B.
[0025] FIG. 9 is a graph of mass flow (g/s) as a function of
aperture size (mm) for the Ginseng composition of Example 2.
[0026] FIG. 10 is a graph of tablet hardness as a function of
compaction force for the compositions of Examples I and 15.
[0027] FIG. 11 is a graph of mass flow (g/s) as a function of
aperture size (mm) for the artichoke extract compositions of
Examples 1 and A.
[0028] FIG. 12 is a graph of moisture uptake for artichoke extract
compositions of Examples 1 and A.
[0029] FIG. 13 is a graph of tablet hardness as a function of
compaction force for the compositions of Examples 16 and G.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0030] Spray dryers are well known in the art for drying
pharmaceutical and nutriceutical active agents and excipients. In
general, a spray dryer is used to process fluid materials into
powders. Typically, the fluid material is introduced into the spray
dryer in the forms of a solution, slurry, suspension, emulsion, or
thin paste. Referring to FIG. 1, a typical spray dryer including a
fluid feed system 1, an atomizer 2, a heated air supply 3, a drying
chamber 4, and a collection system 5. In operation, the fluid
material is fed from the fluid feed system to the atomizer. The
atomizer disperses the fluid material into the drying chamber in
fine droplets. The heated air supply applies heated air to the fine
droplets in the drying chamber, causing the fine droplets to be
dried into a powder, the powder being collected in the collection
system. In certain spray dryers, extremely fine particles that
float up from the collection system (referred to in the art as
"fines") are recycled back into the path of the atomized fluid
material.
[0031] In accordance with an embodiment of the present invention,
the fluid material is an active agent, and silicified
microcrystalline cellulose from (hereinafter "silicified MCC")
from, for example a source of silicified MCC 6, is fed into the
drying chamber 4 and is interdispersed with the atomized fluid
material as the heat 3 is applied. As the atomized fluid material
dries, it is combined with the silicified MCC so that the powder
collected in the collection system 5 includes agglomerated
particles of active agent/silicified MCC.
[0032] As noted above, by fluid (or liquid) material, it is meant
that the material (e.g., the active agent) is sufficiently wetted
to be suitable for subsequent spray drying. For example, the
material may be in a solution, a suspension, a slurry, or an
emulsion. Moreover, the solution may include one or more of a
variety of solvents, including water, alcohol, ethanol, and the
like. Hydro-alcohol solvents may also be used.
[0033] In certain embodiments, dry silicified MCC is fed into the
drying chamber. In another embodiment, a slurry of silicified MCC
(e.g., a slurry of Prosolv SMCC 90) is formed, and the silicified
MCC slurry is fed into the drying chamber as an atomized silicified
MCC fluid. In such an embodiment, the silicified MCC slurry can be
introduced into the drying chamber separately from the atomized
active fluid material (e.g., through a separate spray nozzle), or
the silicified MCC can be combined with the active fluid material
prior to atomization (e.g., as a slurry in the fluid feed system),
and the active fluid material and silicified MCC could be atomized
together.
[0034] In certain embodiments in which dry silicified MCC is fed
into the drying chamber, the dry silicified MCC may be fed into the
drying chamber along with the recycled fines.
[0035] In any event, the silicified MCC is preferably fed into the
drying chamber at a rate sufficient to cause the agglomerated
particles to contain at least about 25% silicified MCC, and
preferably at least about 30% silicified MCC. Most preferably, the
silicified MCC is fed into the drying chamber at a rate sufficient
to cause the agglomerated particles to contain from about 30% to
about 40% silicified MCC.
[0036] In accordance with a further embodiment of the present
invention, dry colloidal silicon dioxide is also fed into the
drying chamber and is interdispersed with the silicified MCC and
the atomized fluid material. Although the use of dry colloidal
silicon dioxide is preferred, in other embodiments, the colloidal
silicon dioxide may be fed into the drying chamber as an atomized
silicon dioxide fluid (e.g., from a slurry). In any event, the
resulting agglomerated particles are agglomerated particles of
active agent/silicified MCC/colloidal silicon dioxide. Preferably,
the silicified MCC and colloidal silicon dioxide is fed into the
drying chamber at a rate sufficient to cause the agglomerated
particles to contain about 25% silicified MCC and about 5%
colloidal silicon dioxide.
[0037] In the context of the present invention, silicified MCC is a
particulate agglomerate of coprocessed microcrystalline cellulose
and from about 0.1% to about 20% silicon dioxide, by weight of the
microcrystalline cellulose, the microcrystalline cellulose and
silicon dioxide being in intimate association with each other, and
the silicon dioxide portion of the agglomerate being derived from a
silicon dioxide having a particle size from about 1 nanometer (nm)
to about 100 microns (.mu.m), based on average primary particle
size. By "intimate association", it is meant that the silicon
dioxide has in some manner been integrated with the
microcrystalline cellulose particles, e.g., via a partial coating
of the microcrystalline particles, as opposed to a chemical
interaction of the two ingredients. The term "intimate association"
is therefore deemed for purposes of the present description as
being synonymous with "integrated" or "united". The coprocessed
particles are not necessarily uniform or homogeneous. Rather, under
magnification, e.g., scanning electron microscope at 500 times, the
silicon dioxide at the preferred percent inclusion appears to be an
"edge-coating". Preferably, the silicon dioxide comprises from
about 0.5% to about 10% of the silicified MCC, and most preferably
from about 1.25% to about 5% by weight relative to the
microcrystalline cellulose. Moreover, the silicon dioxide
preferably has a particle size from about 5 nm to about 40 .mu.m,
and most preferably from about 5 nm to about 50 .mu.m. Moreover,
the silicon dioxide preferably has a surface area from about 10
m.sup.2 g to about 500 m.sup.2/g, preferably from about 50
m.sup.2/g to about 500 m.sup.2/g and more preferably from about 175
m.sup.2/g to about 350 m.sup.2/g. Silicified MCC, and methods for
its manufacture, are described in U.S. Pat. No. 5,585,115, the
entire disclosure of which is hereby incorporated by reference.
Silicified microcrystalline cellulose is commercially available
from Penwest Pharmaceuticals, Inc., under the trademark
Prosolv.RTM.. Prosolv is available in a number of grades,
including, for example, Prosolv SMCC 50, Prosolv SMCC 90, and
Prosolv HD, each of which contains 2% colloidal silicon dioxide, by
weight relative to the microcrystalline cellulose.
[0038] Colloidal silicon dioxide is a submicron fumed silica
prepared by the vapor-phase hydrolysis (e.g., at 1110.degree. C.)
of a silicon compound, such as silicon tetrachloride. The product
itself is a submicron, fluffy, light, loose, bluish-white, odorless
and tasteless amorphous powder which is commercially available from
a number of sources, including Cabot Corporation (under the
tradename Cab-O-Sil); Degussa, Inc. (under the tradename Aerosil);
E. I. DuPont & Co.; and W. R. Grace & Co. Colloidal silicon
dioxide is also known as colloidal silica, fumed silica, light
anhydrous silicic acid, silicic anhydride, and silicon dioxide
fumed, among others. A variety of commercial grades of colloidal
silicon dioxide are produced by varying the manufacturing process.
These modifications do not affect the silica content, specific
gravity, refractive index, color or amorphous form. However, these
modifications are known to change the particle size, surface areas,
and bulk densities of the colloidal silicon dioxide products.
[0039] The surface area of the preferred class of silicon dioxides
utilized in the invention ranges from about 50 m.sup.2/gm to about
5.00 m.sup.2/gm. The average primary particle diameter of the
preferred class of silicon dioxides utilized in the invention
ranges from about 5 nm to about 50 nm. However, in commercial
colloidal silicon dioxide products, these particles are
agglomerated or aggregated to varying extents. The bulk density of
the preferred class of silicon dioxides utilized in the invention
ranges from about 20 g/l to about 100 g/l.
[0040] Commercially available colloidal silicon dioxide products
have, for example) a BET surface area ranging from about 50+-15
m.sup.2/gm (Aerosil OX50) to about 400+-20 (Cab-O-Sil S-17) or
390+-40 m.sup.2/gm (Cab-O-Sil EH-5). Commercially available
particle sizes range from a nominal particle diameter of 7 nm
(e.g., Cab-O-Sil S-17 or Cab-O-Sil EH-5) to an average primary
particle size of 40 nm (Aerosil OX50). The density of these
products range from 72.0+-8 g/l (Cab-O-Sil S-17) to 36.8 g/l (e.g.,
Cab-O-Sil M-5). The pH of the these products at 4% aqueous
dispersion ranges from pH 3.5-4.5. These commercially available
products are described for exemplification purposes of acceptable
properties of the preferred class of silicon dioxides only, and
this description is not meant to limit the scope of the invention
in any manner whatsoever.
[0041] Another type of colloidal silicon dioxide is surface treated
silica, including, for example, hydrophobically modified silica and
hydrophilically modified silica. An example of a commercially
available hydrophobically modified silica that may be used as the
colloidal silicon dioxide in the embodiments described herein is
AEROSIL.RTM. 972, manufactured by Degussa AG.
[0042] The active agent(s) which may be used in accordance with the
embodiments described above include systemically active therapeutic
agents, locally active therapeutic agents, disinfecting agents,
chemical impregnants, cleansing agents, deodorants, fragrances,
dyes, animal repellents, insect repellents, fertilizing agents,
pesticides, herbicides, fungicides, plant growth stimulants, and
the like.
[0043] A wide variety of therapeutically active agents can be used
in conjunction with the present invention. The therapeutically
active agents (e.g. pharmaceutical agents) include both water
soluble and water insoluble drugs. Examples of such therapeutically
active agents include antihistamines (e.g., dimenhydrinate,
diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate),
analgesics (e.g., aspirin, codeine, morphine, dihydromorphone,
oxycodone, etc.), non-steroidal anti-inflammatory agents (e.g.,
naproxyn, diclofenac, indomethacin, ibuprofen, sulindac),
anti-emetics (e.g., metoclopramide), anti-epileptics (e.g.,
phenytoin, meprobamate and nitrezepam), vasodilators (e.g.,
nifedipine, papaverine, diltiazem and nicardirine), anti-tussive
agents and expectorants (e.g., codeine phosphate), anti-asthmatics
(e.g. theophylline), antacids, anti-spasmodics (e.g. atropine,
scopolamine), antidiabetics (e.g., insulin), diuretics (e.g.,
ethacrynic acid, bendrofluazide), anti-hypotensives (e.g.,
propranolol, clonidine), antihypertensives (e.g, clonidine,
methyldopa), bronchodilators. (e.g., albuterol), steroids (e.g.,
hydrocortisone, triamcinolone, prednisone), antibiotics (e.g.,
tetracycline), antihemorrhoidals, hypnotics, psychotropics,
antidiarrheals, mucolytics, sedatives, decongestants, laxatives,
vitamins, stimulants (including appetite suppressants such as
phenylpropanolamine). The above list is not meant to be
exclusive.
[0044] A wide variety of locally active agents can be used in
conjunction with the embodiments described herein, and include both
water soluble and water insoluble agents. The locally active
agent(s) is intended to exert its effect in the environment of use,
e.g., the oral cavity, although in some instances the active agent
may also have systemic activity via absorption into the blood via
the surrounding mucosa.
[0045] The locally active agent(s) include antifungal agents (e.g.,
amphotericin B, clotrimazole, nystatin, ketoconazole, miconazol,
etc.), antibiotic agents (penicillins, cephalosporins,
erythromycin, tetracycline, aminoglycosides, etc.), antiviral
agents (e.g, acyclovir, idoxuridine, etc.), breath fresheners (e.g.
chlorophyll), antitussive agents. (e.g., dextromethorphan
hydrochloride), anti-cariogenic compounds (e.g., metallic salts of
fluoride, sodium monofluorophosphate, stannous fluoride, amine
fluorides), analgesic agents (e.g., methylsalcylate, salicylic
acid, etc.), local anesthetics (e.g., benzocaine), oral antiseptics
(e.g., chlorhexidine and salts thereof, hexylresorcinol,
dequalinium chloride, cetylpyridinium chloride), anti-flammatory
agents (e.g., dexamethasone, betamethasone, prednisone,
prednisolone, triamcinolone, hydrocortisone, etc.), hormonal agents
(oestriol), antiplaque agents (e.g, chlorhexidine and salts
thereof, octenidine, and mixtures of thymol, menthol,
methysalicylate, eucalyptol), acidity reducing agents (e.g.,
buffering agents such as potassium phosphate dibasic, calcium
carbonate, sodium bicarbonate, sodium and potassium hydroxide,
etc.), and tooth desensitizers (e.g., potassium nitrate). This list
is not meant to be exclusive. The solid formulations of the
invention may also include other locally active agents, such as
flavorants and sweeteners. Generally any flavoring or food additive
such as those described in Chemicals Used in Food Processing, pub
1274 by the National Academy of Sciences, pages 63-258 may be used.
Generally, the final product may include from about 0.1% to about
5% by weight flavorant.
[0046] In accordance with one embodiment of the present invention,
the active agent is a liquid herbal extract. As noted above, the
term "liquid" as used herein means that the herbal extract is
sufficiently wetted to be atomized in a spray dryer. Preferably,
the herbal extract is selected from the group consisting of: Alfafa
Leaf, Alfalfa Juice, Aloee-emodin, Andrographolide, Angelica Root,
Astragalus Root, Bilberry, Black Cohosh Root, Black Walnut Leaf,
Blue Cohosh Root, Burdock Root, Cascara Bark, Cats Claw Bark,
Catnip Leaf, Cayenne, Chamomile Flowers, Chaste Tree Berries,
Chickweed, Chinese Red Sage Root, Cranberry, Chrysophanol, Comfrey
Leaf, Cramp Bark, Damiana Leaf, Dandelion Root CO, Devil's Claw
Root, Diosgenin, Dong Quai Root, Dong Quai, Echinacea, Echinacea
Angustifolia Root, Echinacea Purpurea Herb Root and Echinacea
Angust./Purpurea Blend CO, Echinacea Angust./Goldenseal Blend,
Eleuthero (Siberian) Ginseng Root, Emodin, Eyebright Herb,
Fenugreek, Feverfew Herb CO, Of-Ti Root, Of-Ti, Garcinia Cambogia,
Gentian Root, Ginger, Ginko Biloba Ginger Root, Ginseng, Ginko
Leaf, Ginseng Root, Goldenseal Root, Gotu Kola Herb, Grape Seed,
Grape Skin, Green Tea, Green Tea, Decaf, Guarana Seeds, Gynostemma
Pentaphyllum, Hawthorn Berries, Hawthorn Leaf, Hesperdin, Hops
Flowers, Horehound Herb, Horse Chestnut, Horsetail, Hyssop Leaf,
Huperzine A, Juniper Berries, Kava Kava Root, Kola Nut, Lavender
Flowers, Lemon Balm, Licorice Root, Lobelia Herb, Lomatium,
Marshmallow Root, Milk Thistle Seed, Milk Thistle, Mullein Leaf,
Myrrh, Naringin, Neohesperidin, Nettle Leaf, Olive Leaf, Oregon
Grape Root, Papain, Parsley Leaf & Root, Passion Flower, Pau
D'Arco Bark, Pennyroyal, Peppermint Leaf, Physcion, Polystictus
Versicolor Mushroom, Quercetin, Red Clover Blossoms, Red Clover,
Red Raspberry Leaf, Red Yeast Rice, Reishi Mushrooms, Rhein,
Rhubarb Root, Rosemary Leaf, Rutin, Sarsaparilla Root, Saw
Palmetto, Saw Palmetto Berry, Schisandra Berries, Schisandra,
Scullcap Herb, Shavegrass Herb, Sheep Sorrel, Shepard's Purse Herb,
Shitake Mushroom, Slippery Elm Bark, Sown Orange, Soybean, Stevia
Rebaudiana, St. John's Wort, Tetrandrine, Turmeric, Usnea Lichen,
Uva Ursi, Uva Ursi Leaf, Valerian Root, White Willow Bark, Wild Yam
Root, Yellow Dock Root, Yohimbe Bark, Yucca Root, and combinations
thereof. Most preferably, the herbal extract is selected from the
group consisting of St. John's Wort, Artichoke Leaves, and
Ginseng.
[0047] In accordance with certain embodiments of the present
invention, the active agent is hygroscopic. Examples of hygroscopic
active agents include many herbal extracts, including St. John's
Wort, Artichoke Leaves, and Ginseng.
[0048] The agglomerated particles in accordance with the
embodiments of the present invention described above provide a
number of advantages. Specifically, the agglomerated particles
provide superior flow characteristics to prior art compositions. As
one of ordinary skill in the art will appreciate, the superior flow
characteristics provided by the embodiments of the present
invention allow faster and more efficient processing for tablets,
capsules, and other dosage forms.
[0049] The agglomerated particles in accordance with the
embodiments of the present invention also provide superior
compaction characteristics to prior art compositions. As one of
ordinary skill in the art will appreciate the superior compaction
characteristics provided by the embodiments of the present
invention allow faster and more efficient processing for tablets,
and, moreover, allow a larger percentage of active agent to be
included in each tablet. For example, St. John's Wort is currently
marketed in 600 mg capsules, wherein each capsule includes 150 mg.
of St. John's Wort extract. In contrast, in accordance with certain
embodiments of the present invention, 300 mg of St. John's Wort
extract can be included in a 450 mg tablet. Similarly, Ginseng is
currently marketed in 450 mg tablets, wherein each tablet includes
100 mg. of Ginseng extract. In contrast, in accordance with certain
embodiments of the present invention, 500 mg of Ginseng extract can
be included in a 75.2 mg. tablet.
[0050] In addition, the agglomerated particles in accordance with
the embodiments of the present invention exhibit superior content
uniformity when tableted than agglomerated particles that are
formed by a wet granulation of silicified MCC and an active agent.
This is particularly useful when tableting low dose formulations
because such formulations are particularly prone to content
uniformity problems. Thus, the agglomerated particles in accordance
with the embodiments of the present invention are particularly
advantageous with respect to tablets including 100 mg or less
active agent in tablets having a total tablet weight between 200 mg
and 800 mg. In certain embodiments, the tablets include 50 mg or
less active agent in tablets having a total tablet weight of
between 200 mg and 800 mg. In other embodiments, the tablets
include 10 mg or less active agent in tablets having a total tablet
weight of between 50 mg and 800 mg. In still other embodiments, the
tablets include 1 mg or less active agent in tablets having a total
tablet weight of between 10 mg and 800 mg. In still other
embodiments, the tablets include no more than about 20% by weight
active agent, preferably no more than about 10% by weight active
agent, and most preferably no more than about 1% by weight active
agent.
[0051] In accordance with other embodiments of the present
invention, an augmented microcrystalline cellulose can be
substituted for silicified MCC in the above referenced products and
processes. In accordance with these embodiments, the augmented
microcrystalline cellulose is a particulate agglomerate of
coprocessed microcrystalline cellulose and from about 0.1% to about
20% of a compressibility augmenting agent, by weight of the
microcrystalline cellulose, the microcrystalline cellulose and
compressibility augmenting agent being in intimate association with
each other. Examples of suitable compressibility augmenting agents
include pharmaceutically (or nutraceutically) acceptable metal
oxides such as colloidal titanium dioxide, as well as colloidal
carbon black. Surface treated metal oxides may also be used. One
skilled in the art will appreciate that other classes of compounds
having size, surface area, and other similar physical
characteristics to silicon dioxide may also be useful in physically
forming a barrier which may reduce the surface-to-surface
interactions (including hydrogen-bonding) between cellulose
surfaces, and therefore may be used as a compressibility augmenting
agent. It should be appreciated that silicified microcrystalline
cellulose (which includes the metal oxide silicon dioxide) is also
an example of an augmented microcrystalline cellulose as defined
herein.
[0052] In accordance with still other embodiments of the present
invention, pharmaceutically (or nutraceutically) acceptable metal
oxides such as colloidal titanium oxide, or colloidal carbon-black,
can be co-spray dried with the fluid active material and the
silicified MCC (or the other compressibility augmenting agents
described above).
[0053] Although the agglomerated particles in accordance with the
embodiments of the present invention described above are preferably
manufactured using a spray dryer, it should be appreciated that
other types of dryers may alternatively be used, provided that they
are capable of forming the agglomerated particles described
above.
[0054] In accordance with other embodiments of the present
invention, the agglomerated particles described above may be
combined with conventional tableting additives prior to tableting.
For example, if desired, any generally accepted soluble or
insoluble inert pharmaceutical filler (diluent) material can be
included in the final product (e.g., a solid dosage form).
Preferably, the inert pharmaceutical filler comprises a
monosaccharide, a disaccharide, a polyhydric alcohol, inorganic
phosphates, sulfates or carbonates, and/or mixtures thereof.
Examples of suitable inert pharmaceutical fillers include sucrose,
dextrose, lactose, xylitol, fructose, sorbitol, calcium phosphate,
calcium sulfate, calcium carbonate, "off-the-shelf"
microcrystalline cellulose, mixtures thereof, and the like.
[0055] An effective amount of any generally accepted pharmaceutical
lubricant, including the calcium or magnesium soaps may optionally
be added prior to compression into a solid dosage form. The
lubricant may comprise, for example, magnesium stearate in any
amount of about 0.5-3% by weight of the solid dosage form.
[0056] The complete mixture, in an amount sufficient to make a
uniform batch of tablets, may then subjected to tableting in a
conventional production scale tableting machine at normal
compression pressures for that machine, e.g., about 1500-10,000
lbs/sq in. The mixture should not be compressed to such a degree
that there is subsequent difficulty in its hydration when exposed
to gastric fluid.
[0057] The average tablet size for round tablets is preferably
about 50 mg to 500 mg and for capsule-shaped tablets about 200 mg
to 2000 mg. However, other formulations prepared in accordance with
the present invention may be suitably shaped for other uses or
locations, such as other body cavities, e.g., periodontal pockets,
surgical wounds, vaginally. It is contemplated that for certain
uses, e.g., antacid tablets, vaginal tablets and possibly implants,
that the tablet will be larger.
[0058] In certain embodiments of the invention, the tablet is
coated with a sufficient amount of a hydrophobic polymer to render
the formulation capable of providing a release of the medicament
such that a 12 or 24 hour formulation is obtained. In other
embodiments of the present invention, the tablet coating may
comprise an enteric coating material in addition to or instead or
the hydrophobic polymer coating. Examples of suitable enteric
polymers include cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate,
methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose
succinate, cellulose acetate trimellitate, and mixtures of any of
the foregoing. An example of a suitable commercially available
enteric material is available under the trade name Eudragit.TM. L
100-555.
[0059] In further embodiments, the dosage form may be coated with a
hydrophilic coating in addition to or instead of the
above-mentioned coatings. An example of a suitable material which
may be used for such a hydrophilic coating is
hydroxypropylmethylcellulose (e.g., Opadry.RTM., commercially
available from Colorcon, West Point, Pa.).
[0060] The coatings may be applied in any pharmaceutically
acceptable manner known to those skilled in the art. For example,
in one embodiment, the coating is applied via a fluidized bed or in
a coating pan. For example, the coated tablets may be dried, e.g.,
at about 60.degree.-70.degree. C. for about 3-4 hours in a coating
pan. The solvent for the hydrophobic polymer or enteric coating may
be organic, aqueous, or a mixture of an organic and an aqueous
solvent. The organic solvents may be, e.g., isopropyl alcohol,
ethanol, and the like, with or without water.
[0061] The coatings which may be optionally applied to the
compressed solid dosage form of the invention may comprise from
about 0.5% to about 30% by weight of the final solid dosage
form.
[0062] In additional embodiments of the present invention, a
support platform is applied to the tablets manufactured in
accordance with the present invention. Suitable support platforms
are well known to those skilled in the art. An example of suitable
support platforms is set forth, e.g., in U.S. Pat. No. 4,839,177,
hereby incorporated by reference. In that patent, the support
platform partially coats the tablet, and consists of a polymeric
material insoluble in aqueous liquids. The support platform may,
for example, be designed to maintain its impermeability
characteristics during the transfer of the therapeutically active
medicament. The support platform may be applied to the tablets,
e.g., via compression coating onto part of the tablet surface, by
spray coating the polymeric materials comprising the support
platform onto all or part of the tablet surface, or by immersing
the tablets in a solution of the polymeric materials.
[0063] The support platform may have a thickness of, e.g., about 2
mm if applied by compression, and about 10 .mu.m if applied via
spray-coating or immersion-coating. Generally, in embodiments of
the invention wherein a hydrophobic polymer or enteric coating is
applied to the tablets, the tablets are coated to a weight gain
from about 1% to about 20%, and in certain embodiments preferably
from about 5% to about 10%.
[0064] Materials useful in the hydrophobic coatings and support
platforms of the present invention include derivatives of acrylic
acid (such as esters of acrylic acid, methacrylic acid, and
copolymers thereof) celluloses and derivatives thereof (such as
ethylcellulose), polyvinylalcohols, and the like.
[0065] In certain embodiments of the present invention, an
additional dose of the active agent may be included in either the
hydrophobic or enteric coating, or in an additional overcoating
coated on the outer surface of the tablet core (without the
hydrophobic or enteric coating) or as a second coating layer coated
on the surface of the base coating comprising the hydrophobic or
enteric coating material. This may be desired when, for example, a
loading dose of a therapeutically active agent is needed to provide
therapeutically effective blood levels of the active agent when the
formulation is first exposed to gastric fluid. The loading dose of
active agent included in the coating layer may be, e.g., from about
10% to about 40% of the total amount of medicament included in the
formulation.
[0066] The tablets of the present invention may also contain
effective amounts of coloring agents, (e.g., titanium dioxide, F.
D. & C. and D. & C. dyes; see the Kirk-Othmer Encyclopedia
of Chemical Technology, Vol. 5, pp. 857-884, hereby incorporated by
reference), stabilizers, binders, odor controlling agents, and
preservatives.
[0067] Alternatively, the agglomerated particles of active
agent/silicified MCC (with or without silicon dioxide) can be
utilized in other applications wherein it is not compressed. For
example, the agglomerated particles can be filled into capsules.
The agglomerated particles can further be molded into shapes other
than those typically associated with tablets. For example, the
agglomerated particles can be molded to "fit" into a particular
area in an environment of use (e.g., an implant). All such uses
would be contemplated by those skilled in the art and are deemed to
be encompassed within the scope of the appended claims.
EXAMPLES 1 THROUGH 16 AND A THROUGH K
Example 1
[0068] Agglomerated particles of artichoke leaves extract/Prosolv
SMCC 90/silicon dioxide were prepared with the following
ingredients: TABLE-US-00001 Product Amount/kg Artichoke Leaves
Extract: Extr. 100.0 (70.0) Cynarae e fol aquos. spiss. (Content of
dry substance 70.0%, corresponding to dry substance) Prosolv SMCC
90 30.0 Silicon dioxide, highly dispersed (Aerosil) Ph. Eur.
5.0
[0069] The artichoke leaves extract is in the form of a liquid
extract (specifically, it is in a water solvent). This liquid
extract was placed into the fluid feed system of a spray dryer,
atomized, and combined with the Prosolv SMCC 90 and colloidal
silicon dioxide in the drying chamber of the spray dryer. In this
example, the Prosolv SMCC 90 and colloidal silicon dioxide (both
dry) were homogenized (in a mixer), and then fed into the drying
chamber along with the recycled fines from the collection
system.
[0070] The agglomerated particles collected from the collection
system provided a yield of 95.2 kg, with the following composition:
[0071] 70.0% Artichoke Leaves extract (Extr. Cynarae e fol aquos.
spiss) [0072] 25.0% Prosolv (SMCC 90) [0073] 5.0% Silicon dioxide,
highly dispersed, Ph. Eur.
Comparative Example A
[0074] A mixture of artichoke leaves
extract/glucose/maltodextrin/silicon dioxide was prepared with the
following ingredients: TABLE-US-00002 Product Amount/kg Extr.
Cynarae e fol aquos. spiss. 834.0 (557.9) (Content of dry substance
66.9%, corresponding to dry substance) Glucose sirup Ph. Eur.,
dried 124.8 (118.6) (Content of dry substance 95%, corresponding to
dry substance) Silicon dioxide, highly dispersed Batch 1 20.9
(Aerosil), Ph. Eur Batch 2 11.5 Maltodextrin Ph. Eur. (DE 11-16)
373.0
[0075] The artichoke leaves extract is in the form of a liquid
extract (specifically, it is in a water solvent). This liquid
extract was placed into the fluid feed system of a spray dryer,
atomized, and combined with the 20.9 g of colloidal silicon dioxide
in the drying chamber of the spray dryer. The resultant
agglomerated particles were then mixed with the glucose,
maltodextrin, and the remaining 11.5 g of colloidal silicon dioxide
in a mixer.
[0076] The resulting mixture provided a yield of 1036.5 kg with the
following composition: [0077] 51.6% Artichoke Leaves extract (Extr.
Cynarae e fol aquos. spiss) [0078] 10.9% Glucose sirup Ph. Eur.,
dried [0079] 34.5% Maltodextrin Ph. Eur. [0080] 3.0% Silicon
dioxide, highly dispersed (Aerosil), Ph. Eur.
Example 2
[0081] Agglomerated particles of ginseng extract/Prosolv SMCC
90/silicon dioxide were prepared with the following ingredients:
TABLE-US-00003 Product Amount/kg Extr. Ginseng e rad. spir. spiss.
50.0 (36.5) (Content of dry substance 73.0%, corresponding to dry
substance:) Extr. Ginseng e rad. spir. spiss. 50.0 (36.0) (Content
of dry substance 72.0%, corresponding to dry substance:) Prosolv
SMCC 90 25.9 Silicon dioxide, highly dispersed (Aerosil), Ph. Eur.
5.2
[0082] The ginseng extract is in the form of a liquid extract
(specifically, it is in an Ethanol 60% (V/V) solvent). This liquid
extract was placed into the fluid feed system of a spray dryer,
atomized, and combined with the Prosolv SMCC 90 and colloidal
silicon dioxide in the drying chamber of the spray dryer. In this
example, the Prosolv SMCC and colloidal silicon dioxide (both dry)
were homogenized (in a mixer), and then fed into the drying chamber
along with the recycled fines from the collection system.
[0083] The agglomerated particles collected from the collection
system provided a yield of 94.4 kg, with the following composition:
[0084] 70.0% Ginseng extract (Extr. Ginseng e rad. spir. spiss.)
[0085] 25.0% Prosolv SMCC 90 [0086] 5.0% Silicon dioxide, highly
dispersed
Comparative Example B
[0087] A mixture of ginseng extract/maltodextrin was prepared with
the following ingredients: TABLE-US-00004 Product Amount/kg Radix
Ginseng, >=7% Ginsenosides batch 1 110 (HPLC), >=50% Ratio
batch 2 550 of Rg1 to Rb1: batch 3 867 batch 4 842 (=526 kg native
extract) Maltodextrin USP 18 total amount 544
[0088] The ginseng extract is in the form of a liquid extract
(specifically, it is in an Ethanol 70% (V/V) solvent). The liquid
extract was mixed with the maltodextrin in a mixture, then dried in
a vacuum belt dryer and milled. The resultant product had a yield
of 517.5 kg, with the following composition: [0089] 96.7% Ginseng
extract [0090] 3.3% maltodextrin USP
Example 3
[0091] Agglomerated particles of St. John's Wort extract/Prosolv
SMCC 90 were prepared with the following ingredients:
TABLE-US-00005 Product Amount/kg Extr. Hyperici e herb. spir.
spiss. 216.0 (105.2) (Content of dry substance 48.7%, corresp. to
dry substance) Prosolv SMCC 90 45.1
[0092] The St. John's Wort extract is in the form of a liquid
extract (specifically, it is in an Ethanol 60% (m/m) solvent). This
liquid extract was placed into the fluid feed system of a spray
dryer, atomized, and combined with the Prosolv SMCC 90 in the
drying chamber of the spray dryer. In this example, dry Prosolv
SMCC (dry) was fed into the drying chamber along with the recycled
fines from the collection system.
[0093] The agglomerated particles collected from the collection
system provided a yield of 138.8 kg, with the following
composition: [0094] 70% St. John's Wort extract (Extr. Hyperici e
herb. spir. spiss.) [0095] 30% Prosolv (SMCC 90)
Example 4
[0096] Agglomerated particles of St. John's Wort extract/Prosolv
SMCC 90 were prepared with the following ingredients:
TABLE-US-00006 Product Amount/kg Extr. Hyperici e herb. spir.
spiss. 305.0 (110.7) (Content of dry substance 36.3%, corresponding
to dry substance:) Prosolv SMCC 90 batch 1 2.9 batch 2 48.5
[0097] The St. John's Wort extract is in the form of a liquid
extract (specifically, it is in an Ethanol 60% (m/m) solvent). This
liquid extract was placed into the fluid feed system of a spray
dryer, atomized, and combined with the Prosolv SMCC 90 in the
drying chamber of the spray dryer. In this example, dry Prosolv
SMCC (dry) was fed into the drying chamber along with the recycled
fines from the collection system.
[0098] The agglomerated particles collected from the collection
system provided a yield of 176.6 kg, with the following
composition: [0099] 68.3% St. John's Wort extract (Extr. Hyperici e
herb. spir. spiss.) [0100] 31.7% Prosolv SMCC 90
Example 5
[0101] Agglomerated particles of St. John's Wort extract/Prosolv
SMCC 90/silicon dioxide were prepared with the following
ingredients: TABLE-US-00007 Product Amount/kg Extr. Hyperici e
herb. spir. spiss. 297.5 (127.9) (Content of dry substance 43.0%,
corresponding to dry substance:) Prosolv SMCC 90 45.5 Silicon
dioxide, highly dispersed (Aerosil), Ph. Eur 9.5
[0102] The St. John's Wort extract is in the form of a liquid
extract (specifically, it is in an Ethanol 60% (m/m) solvent). This
liquid extract was placed into the fluid feed system of a spray
dryer, atomized, and combined with the Prosolv SMCC 90 and
colloidal silicon dioxide in the drying chamber of the spray dryer.
In this example, the Prosolv SMCC and colloidal silicon dioxide
(both dry) were homogenized (in a mixer), and then fed into the
drying chamber along with the recycled fines from the collection
system.
[0103] The agglomerated particles collected from the collection
system provided a yield of 152.8 kg, with the following
composition: [0104] 69.9% St. John's Wort extract (Extr. Hyperici e
herb. spir. spiss.) [0105] 24.9% Prosolv (SMCC 90) [0106] 5.2%
Silicon dioxide, highly dispersed (Aerosil), Ph. Eur.
Comparative Example C
[0107] A mixture of St. John's extract/maltodextrin/silicon dioxide
was prepared with the following ingredients: TABLE-US-00008 Product
Amount/kg Extr. Hyperici e herb. spir. spiss. 5000.0 (2025.0)
(Content of dry substance 40.5%, corresponding to dry substance:)
Silicon dioxide, highly dispersed (Aerosil), Ph. Eur. 104.6
Maltodextrin Ph. Eur. 100.0
[0108] The St. John's Wort extract is in the form of a liquid
extract (specifically, it is in a Ethanol 60% (m/m) solvent). This
liquid extract was placed into the fluid feed system of a spray
dryer, atomized, and combined with the colloidal silicon dioxide in
the drying chamber of the spray dryer. The resultant agglomerated
particles were then mixed with the maltodextrin in a mixer.
[0109] The mixture provided a yield of 2109.8 kg, with the
following composition: [0110] 90.8% St. John's Wort extract (Extr.
Hyperici e herb. spir. spiss.) [0111] 4.7% Silicon dioxide, highly
dispersed, Ph. Eur. [0112] 4.5% Maltodextrin Ph. Eur.
Comparative Example D
[0113] A mixture of St. John's extract/maltodextrin/silicon dioxide
was prepared with the following ingredients: TABLE-US-00009 Product
Amount/kg Extr. Hyperici e herb. spir. spiss. 402.2 (170.5)
(Content of dry substance 42.4%, corresponding to dry substance:)
Extr. Hyperici e herb. spir. spiss. 367.6 (156.6) (Content of dry
substance 42.6%, corresponding to dry substance) Extr. Hyperici e
herb. spir. spiss. 540.2 (227.9) (Content of dry substance 42.2%,
corresponding to dry substance::) Extr. Hyperici e herb. spir.
spiss. 722.3 (456.5) (Content of dry substance 63.2%, corresponding
to dry substance::) Silicon dioxide, highly dispersed, Batch 1 12.3
(Aerosil) Ph. Eur. Batch 2 8.0 Batch 3 39.6 Maltodextrin Ph. Eur.
Batch 1 557.8 Batch 2 3.7
[0114] The St. John's Wort extract is in the form of a liquid
extract (specifically, it is in a Ethanol 60% (m/m) solvent). This
liquid extract was placed into the fluid feed system of a spray
dryer, atomized, and combined with the colloidal silicon dioxide
(Batches 1-3) in the drying chamber of the spray dryer. The
resultant agglomerated particles were then mixed with the
maltodextrin (Batches 1-2) in a mixer.
[0115] The mixture provided a yield of 1588.2 kg, with the
following composition: [0116] 62.0% St. John's Wort extract (Extr.
Hyperici e herb. spir. spiss.) [0117] 34.4% Maltodextrin Ph. Eur.
[0118] 3.6% Silicon dioxide Ph. Eur.
Example 6
[0119] In Example 6, the agglomerated particles of Example 3 are
mixed in a Patterson-Kelley twin-shell V-blender with MgStearate
and Maltodextrin to form a mixture with the following composition:
TABLE-US-00010 Ingredient amount(g) percentage Example 3 278.60
69.65% Maltodextrin 119.40 29.85% Mg Stearate 2.00 0.50% Total
400.00 100%
Example 7
[0120] In Example 7, the agglomerated particles of Example 3 are
mixed in a Patterson-Kelley twin-shell V-blender with MgStearate
and Prosolv SMCC 50 to form a mixture with the following
composition: TABLE-US-00011 Ingredient amount(g) percentage Example
3 306.69 76.67% PROSOLV SMCC 50 91.31 22.83% Mg Stearate 2.00 0.50%
Total 400.00 100%
Comparative Example E
[0121] In Example E, the mixture Example D is mixed in a
Patterson-Kelley twin-shell V-blender with MgStearate and Prosolv
SMCC 50 to form a mixture with the following composition:
TABLE-US-00012 Ingredient amount(g) percentage Example D 278.60
69.65% PROSOLV SMCC 50 119.40 29.85% Mg Stearate 2.00 0.50% Total
400.00 100%
Example 8
[0122] In Example 8, the agglomerated particles of Example 3 are
mixed in a Patterson-Kelley twin-shell V-blender with MgStearate to
form a mixture with the following composition: TABLE-US-00013
Ingredient amount(g) percentage Example 3 398.00 99.50% Mg Stearate
2.00 0.50% Total 400.00 100%
Comparative Example F
[0123] In Example F, the mixture of Example D is mixed in a
Patterson-Kelley twin-shell V-blender with MgStearate to form a
mixture with the following composition: TABLE-US-00014 Ingredient
amount(g) percentage Example D 398.00 99.50% Mg Stearate 2.00 0.50%
Total 400.00 100%
Example 9
[0124] In Example 9-1, the agglomerated particles of Example 5 are
mixed in a Patterson-Kelley twin-shell V-blender with Explotab for
ten minutes and then MgStearate is added to the mixture and blended
for 5 minutes to form a mixture with the following composition:
TABLE-US-00015 Ingredient amount percentage Example 5 386 96.50%
Explotab 12 3.00% Mg Stearate 2 0.50% Total 400 100%
[0125] In Example 9-2, the agglomerated particles of Example 5 are
mixed in a Patterson-Kelley twin-shell V-blender with Explotab for
ten minutes and then MgStearate is added to the mixture and blended
for 5 minutes to form a mixture with the following composition:
TABLE-US-00016 Ingredient amount percentage Example 5 723.75 96.5%
Explotab 22.50 3.0% Mg Stearate 3.75 0.5% Total 750.00 100%
Comparative Example G
[0126] In Example G, the mixture of the of Example A is mixed in a
Patterson-Kelley twin-shell V-blender with Prosolv SMCC 50, sodium
stearyl fumate and MgStearate to form a mixture with the following
composition: TABLE-US-00017 Ingredient amount(g) percentage Example
A 384 96.00% sodium stearyl fumate 8 2.00% talc 8 2.00% Total 400
100%
Example 10
[0127] Example 10 was produced in the same manner as Examples 3 and
4, except that the agglomerated particles collected from the
collection system had the following composition: [0128] 80.0% St.
John's Wort extract (Extr. Hyperici e herb. spir. spiss.) [0129]
20.0% Prosolv SMCC 90
Example 11
[0130] Example 11 was produced in the same manner as Examples 3 and
4, except that the agglomerated particles collected from the
collection system had the following composition: [0131] 75.0% St.
John's Wort extract (Extr. Hyperici e herb. spir. spiss.) [0132]
25.0% Prosolv SMCC 90
Example 12
[0133] In Example 12, the agglomerated particles of Example 4 are
mixed in a Patterson-Kelley twin-shell V-blender with Explotab for
ten minutes and then MgStearate is added to the mixture and blended
for 5 minutes to form a mixture with the following composition:
TABLE-US-00018 Ingredient amount(g) percentage Example 4 723.75
96.5% Explotab 22.50 3.0% Mg Stearate 3.75 0.5% Total 750.00
100%
Comparative Example H
[0134] In Example H, the mixture of Comparative Example D is mixed
in a Patterson-Kelley twin-shell V-blender with Explotab for ten
minutes and then MgStearate is added to the mixture and blended for
5 minutes to form a mixture with the following composition:
TABLE-US-00019 Ingredient amount(g) percentage Example D 723.75
96.5% Explotab 22.50 3.0% Mg Stearate 3.75 0.5% Total 750.00
100%
Example 13
[0135] In Example 13, the agglomerated particles of Example 11 are
mixed in a Patterson-Kelley twin-shell V-blender with Explotab for
ten minutes and then MgStearate is added to the mixture and blended
for 5 minutes to form a mixture with the following composition:
TABLE-US-00020 Ingredient amount percentage Example 11 723.75 96.5%
Explotab 22.50 3.0% Mg Stearate 3.75 0.5% Total 750.00 100%
Example 14
[0136] In Example 14, the agglomerated particles of Example 10 are
mixed in a Patterson-Kelley twin-shell V-blender with Explotab for
ten minutes and then MgStearate is added to the mixture and blended
for 5 minutes to form a mixture with the following composition:
TABLE-US-00021 Ingredient amount(g) percentage Example 10 723.75
96.5% Explotab 22.50 3.0% Mg Stearate 3.75 0.5% Total 750.00
100%
Comparative Example I
[0137] In Example I, the mixture of Example B is mixed in a
Patterson-Kelley twin-shell V-blender for five minutes with Prosolv
SMCC 50, sodium stearyl fumate and MgStearate to form a mixture
with the following composition: TABLE-US-00022 Ingredient amount(g)
percentage Example B 264 66.00% sodium stearyl fumate 8 2.00% talc
8 2.00% Prosolv SMCC 50 120 30.00% Total 400 100%
Comparative Example J
[0138] In Example J, the mixture of Example B is mixed in a
Patterson-Kelley twin-shell V-blender with Prosolv SMCC 50 to form
a mixture with the following composition: TABLE-US-00023 Ingredient
amount(g) percentage Example B 66.92 70.00% Prosolv SMCC 50 28.68
30.00% Total 95.6 100%
Example 15
[0139] In Example 15, the agglomerated particles of Example 2 are
mixed in a Patterson-Kelley twin-shell V-blender with sodium
stearyl fumate and MgStearate for five minutes to form a mixture
with the following composition: TABLE-US-00024 Ingredient amount(g)
percentage Example 2 384 96.00% sodium stearyl fumate 8 2.00% talc
8 2.00% Total 400 100%
Example 16
[0140] In Example 16, the agglomerated particles of Example 1 are
mixed in a Patterson-Kelley twin-shell V-blender with sodium
stearyl fumate and MgStearate for five minutes to form a mixture
with the following composition: TABLE-US-00025 Ingredient amount(g)
percentage Example 1 384 96.00% sodium stearyl fumate 8 2.00% talc
8 2.00% Total 400 100%
[0141] The examples set forth above were subjected to tests to
evaluate their flow characteristics, moisture uptake
characteristics, and compaction characteristics. The results are
described below in connection with FIGS. 2 through 13.
St. John's Wort Extract Formulations
[0142] FIG. 2 is a graph of volume flow (ml/s) as a function of
aperture size (mm) for the St. John's Wort compositions of Examples
3 and D. The compositions of Example 3 and Example D each had an
initial mass of 75.00 g and a bulk density 0.465 g/ml. The flodex
cup diameter used for each example was 5.7 cm. The relative
humidity during the testing of Example 3 was 65% RH, whereas the
relative humidity during the testing of Example D was 45% RH.
Flow Data For Example 3
[0143] TABLE-US-00026 Mass Volume Avg. Trial 1 Trial 2 Trial 3 flow
flow retained Drained Apert. time mass time mass time mass rate
rate mass angle of (mm) (s) (g) (s) (g) (s) (g) (g s-1) (ml s-1)
(g) repose 26 2.00 66.50 1.87 65.90 2.19 66.50 32.95 70.89 8.70
33.degree. 24 1.75 64.80 2.00 64.90 2.41 67.60 32.51 69.94 9.23
34.degree. 22 2.59 65.20 2.09 66.00 2.55 66.00 27.55 59.26 9.27
33.degree. 20 3.03 62.20 3.05 64.80 2.88 60.90 20.97 45.12 12.37
39.degree. 18 3.08 62.40 3.15 63.40 3.09 63.20 20.28 43.63 12.00
37.degree. 16 3.66 61.00 3.97 62.00 3.75 62.00 16.27 35.01 13.33
39.degree. 14 5.53 60.70 4.69 60.60 4.69 58.60 12.13 26.10 15.03
41.degree. 12 6.85 59.20 6.44 58.00 6.88 57.90 8.69 18.69 16.63
43.degree. 10 9.65 54.60 9.75 53.30 9.62 57.60 5.70 12.27 19.83
47.degree. 9 11.63 54.50 11.69 54.90 11.94 55.90 4.69 10.09 19.90
46.degree. 8 16.18 55.50 16.44 56.10 15.94 48.80 3.30 7.10 21.53
48.degree.
Flow Data For Example D
[0144] TABLE-US-00027 Mass Volume Avg. Trial 1 Trial 2 Trial 3 flow
flow retained Drained Apert. time mass time mass time mass rate
rate mass angle of (mm) (s) (g) (s) (g) (s) (g) (g s-1) (ml s-1)
(g) repose 26 1.53 70.17 1.38 67.30 1.47 73.20 48.14 103.58 4.78
20.degree. 24 1.69 70.30 1.68 66.30 1.60 66.00 40.77 87.72 7.47
28.degree. 22 2.12 62.30 2.63 64.90 2.1 63.60 28.12 60.49 11.40
38.degree. 20 2.1 59.70 2.47 62.40 2.44 62.40 26.42 56.85 13.50
42.degree. 18 3.41 61.70 3.28 56.90 3.15 58.40 17.99 38.71 16.00
45.degree. 16 Bridged
[0145] As shown in FIG. 2, the St. John's Wort extract coprocessed
with silicified MCC in accordance with the present invention
(Example 3) exhibits superior flow characteristics to the St.
John's Wort which is not coprocessed with silicified MCC
(Comparative Example D). In particular, the St. John's Wort of
Example D that was co-sprayed dried with silicon dioxide, and
thereafter mixed with maltodextrin was unable to flow though a 16
mm aperture (in other words, Example D bridged at 16 mm). In
contrast, the St. John's Wort extract of Example 3 did not bridge
until 7 mm, despite the fact that the testing of Example 3 were
conducted at a higher relative humidity.
[0146] FIG. 3 is a graph of volume flow (ml/s) as a function of
aperture size (mm) for the St. John's Wort compositions of Examples
6, 7, and E. The flow data was collected using a Hanson Flodex.TM.
(Hanson Research Instruments, Inc.). The flodex cup diameter used
for each composition was 5.7 cm, and each composition had an
initial mass of 75.00 g. The composition of Example E had a bulk
density of 0.476 g/ml, the composition of Example 6 had a bulk
density of 0.468 g/ml, and the composition of Example 7 had a bulk
density of 0.432 g/ml. All tests were conducted on the same day,
with the relative humidity ranging from 45% to 48% RH.
Flow Data For Example 6
[0147] TABLE-US-00028 Mass Volume Avg. Trial 1 Trial 2 Trial 3 flow
flow retained Drained Apert. time mass time mass time mass rate
rate mass angle of (mm) (s) (g) (s) (g) (s) (g) (g s-1) (ml s-1)
(g) repose 26 1.28 63.50 1.23 63.60 1.43 63.10 48.48 103.59 11.60
41.degree. 24 1.56 62.40 1.51 61.60 1.34 62.50 42.48 90.77 12.83
43.degree. 22 1.90 60.40 1.97 60.90 1.75 58.60 32.06 68.51 15.03
46.degree. 20 2.28 60.40 2.13 58.70 2.15 57.00 26.85 57.38 16.30
47.degree. 18 2.44 57.20 2.19 52.90 2.25 54.20 23.90 51.06 20.23
52.degree. 16 2.59 53.80 2.62 54.10 2.62 49.20 20.07 42.88 22.63
54.degree. 14 3.50 53.90 3.15 48.80 3.23 48.70 15.32 32.74 24.53
55.degree. 12 4.38 43.00 4.54 48.70 4.34 45.20 10.32 22.05 29.37
58.degree. 10 7.44 44.30 7.40 44.60 7.37 42.50 5.92 12.64 31.20
59.degree. 9 10.97 49.80 8.62 41.10 8.44 43.40 4.82 10.29 30.23
58.degree. 8 13.50 48.70 12.59 46.30 12.35 42.90 3.59 7.66 29.03
56.degree. 7 16.35 44.30 15.53 46.40 14.72 42.10 2.85 6.09 30.73
57.degree. 6 22.06 42.40 21.22 40.80 21.44 41.00 1.92 4.10 33.60
59.degree. 5 34.18 40.60 35.13 40.90 38.18 40.00 1.13 2.42 34.50
59.degree. 4 52.47 38.80 50.91 37.00 37.00 39.90 0.85 1.81 36.43
60.degree.
Flow Data For Example 7
[0148] TABLE-US-00029 Mass Volume Avg. Drained Trial 1 Trial 2
Trial 3 flow flow retained angle of Apert. time mass time mass time
mass rate rate mass repose 26 1.63 63.20 1.91 62.70 1.56 62.80
37.29 86.31 12.10 44.degree. 24 1.91 58.70 1.66 61.30 1.97 60.10
32.72 75.75 14.97 49.degree. 22 2.50 61.50 1.97 58.60 2.00 60.00
28.12 65.08 14.97 48.degree. 20 2.59 58.20 2.15 56.80 2.25 56.90
24.73 57.24 17.70 52.degree. 18 2.32 54.30 2.34 54.10 2.75 56.90
22.41 51.86 19.90 54.degree. 16 3.16 54.20 2.91 51.60 2.85 54.70
18.03 41.73 21.50 55.degree. 14 3.65 52.20 3.81 48.70 3.85 51.10
13.45 31.14 24.33 57.degree. 12 6.00 52.30 6.06 50.10 5.71 50.50
8.61 19.93 24.03 55.degree. 10 9.69 51.50 9.85 52.40 9.18 44.40
5.16 11.94 25.57 56.degree. 9 13.22 51.30 10.72 43.10 11.56 48.80
4.04 9.35 27.27 57.degree. 8 15.35 49.80 13.94 40.90 14.37 41.40
3.02 6.99 30.97 60.degree. 7 22.37 49.80 18.34 39.40 19.72 42.90
2.18 5.05 30.97 59.degree. 6 27.28 40.20 26.57 39.80 27.15 39.00
1.47 3.40 35.33 62.degree. 5 44.34 39.60 41.91 39.20 48.47 43.60
0.91 2.10 34.20 61.degree. 4 68.06 37.50 66.15 36.40 72.43 39.60
0.55 1.27 37.17 62.degree.
Flow Data For Example E
[0149] TABLE-US-00030 Mass Volume Avg. Drained Trial 1 Trial 2
Trial 3 flow flow retained angle of Apert. time mass time mass time
mass rate rate mass repose 26 1.32 53.60 1.28 52.20 1.38 54.30
40.25 84.55 21.63 58.degree. 24 1.69 51.80 1.50 53.20 1.50 54.60
34.17 71.79 21.80 57.degree. 22 2.38 52.10 1.75 49.80 1.90 50.50
25.64 53.87 24.20 58.degree. 20 1.94 46.00 2.06 47.90 2.04 47.20
23.37 49.09 27.97 61.degree. 18 3.31 46.80 2.69 41.10 2.22 42.30
16.16 33.94 31.60 63.degree. 16 BRIDGED
[0150] As shown in FIG. 3, when the St. John's Wort composition of
Example 3 is further mixed with maltodextrin and MgStearate
(Example 6) or with silicified MCC and Mg Stearate (Example 7), the
resultant formulation continued to flow even through the minimum
aperture of 4 mm. In contrast, mixing the St. John's Wort extract
of Example D with silicified MCC (Example E) had no appreciable
effect on flow, as the resultant formulation continued to bridge at
16 mm.
[0151] FIG. 4 is a graph of moisture uptake for the St. John's wort
compositions. Twenty-five gram samples of Examples 4 and D were
maintained at 25 C and 40% RH. As shown in FIG. 4, the St. John's
Wort extract that was co-sprayed dried with silicified MCC (Example
4) has acceptable moisture uptake when compared the St. John's Wort
extract which was not co-spray dried with silicified MCC (Example
D). In general, it is considered desirable to have acceptable
moisture uptake because unacceptably high levels of moisture
absorption may lead to stability problems with the final dosage
form, and can cause adverse affects during tableting such as
caking.
[0152] FIGS. 5 through 7 are graphs of tablet hardness as a
function of compaction force for Examples 7-9, 12-14, and H.
[0153] FIG. 5 is a graph of tablet hardness as a function of
compaction force for the compositions of Examples 7 and E. Each
composition was tableted in a caplet shaped 0.250''.times.0.750'',
and the tablets had a target tablet mass of 550 mg. The compaction
data for each formulation is set forth below:
Compaction Data For Example E
[0154] TABLE-US-00031 Compaction Std. dev. Tablet hardness Std.
dev. Avg. Tablet mass force (kN) (kN) (kp) (kp) (mg) 9.21 0.24 2.75
0.00 553.14 14.88 0.63 7.47 0.01 555.32 19.19 0.52 7.99 0.01 545.62
27.92 0.63 13.70 0.01 554.62 29.21 0.54 13.74 0.01 547.48
Compaction Data For Example 7
[0155] TABLE-US-00032 Compaction Std. dev. Tablet hardness Std.
dev. Avg. Tablet mass force (kN) (kN) (kp) (kp) (mg) 10.35 0.19
6.75 0.01 550.22 15.62 0.20 15.75 0.00 551.01 20.88 0.38 21.30 0.01
548.03 24.22 0.34 24.08 0.01 555.37 31.18 0.26 25.91 0.00
549.99
[0156] As shown in FIG. 5 and the above data, the St. John's Wort
co-spray dried with 30% silicified MCC exhibits superior compaction
and hardness characteristics, when tableted with MgStearate and
silicified MCC (Example 7), than a St. John's Wort extract that is
tableted in the same manner, but is not co-spray dried with
silicified MCC (Example E).
[0157] FIG. 6 is a graph of tablet hardness as a function of
compaction force for the compositions of Examples 8, 9-1, and F.
Each composition was tableted in a caplet shaped
0.250''.times.0.750'', and the tablets had a target tablet mass of
550 mg. The compaction data for each formulation is set forth
below:
Compaction Data For Example 8
[0158] TABLE-US-00033 Compaction Std. dev. Tablet hardness Std.
dev. Avg. Tablet mass force (kN) (kN) (kp) (kp) (mg) 9.61 0.04 3.83
0.00 545.81 15.90 0.19 9.80 0.01 545.96 22.89 0.12 16.07 0.01
549.83 25.45 0.10 17.39 0.00 545.44 32.15 0.24 19.19 0.00
545.34
Compaction Data For Example 9-1
[0159] TABLE-US-00034 Compaction Std. dev. Tablet hardness Std.
dev. Avg. Tablet mass force (kN) (kN) (kp) (kp) (mg) 9.52 0.20
10.23 1.66 551.24 14.43 0.62 17.18 1.66 549.67 21.52 1.90 25.48
2.38 547.77 26.29 1.76 29.91 2.22 553.42 29.06 1.64 30.35 0.96
548.12
Compaction Data For Example F
[0160] TABLE-US-00035 Compaction Std. dev. Tablet hardness Std.
dev. Avg. Tablet mass force (kN) (kN) (kp) (kp) (mg) 13.55 2.15
2.59 0.01 554.97 16.54 1.34 4.26 0.01 545.79 22.25 1.04 6.26 0.01
545.78 25.27 0.70 8.30 0.01 552.25 30.55 0.73 8.52 0.01 546.23
[0161] As shown in FIG. 6 and the above data, the St. John's Wort
co-spray dried with 30% silicified MCC exhibits superior compaction
and hardness characteristics, when tableted with MgStearate
(Example 8), than a St. John's Wort extract that is tableted in the
same manner, but is not co-spray dried with silicified MCC (Example
F). In addition, when the St. John's Wort that was co-spray dried
with silicified MCC and colloidal silicon dioxide (Example 9-1) was
tableted with MgStearate and Explotab, it exhibited superior
compaction and hardness characteristics to both Example 8 and
Example F.
[0162] FIG. 7 is a graph of tablet hardness as a function of
compaction force for the compositions of Examples 9-2, 12, 13,-14,
and H. Each composition was tableted in a caplet shaped
0.2230''.times.0.5670'' and the tablets had a target tablet mass of
441 mg. The compaction data for each formulation is set forth
below:
Compaction Data For Example 9-2
[0163] TABLE-US-00036 Compaction Std. dev. Tablet hardness Std.
dev. Avg. Tablet mass force (kN) (kN) (kp) (kp) (mg) 8.13 1.63 6.44
0.50 443.17 9.71 0.33 7.93 0.74 441.75 14.03 0.32 17.06 1.46 436.69
18.99 0.30 23.80 8.55 434.97 26.27 0.29 27.98 2.46 435.47 30.52
0.57 30.13 1.85 440.33 33.71 0.38 30.00 1.99 444.91
Compaction Data For Example 12
[0164] TABLE-US-00037 Compaction Std. dev. Tablet hardness Std.
dev. Avg. Tablet mass force (kN) (kN) (kp) (kp) (mg) 5.95 0.12 4.90
0.91 436.09 10.53 0.22 10.58 0.27 446.32 15.99 0.38 11.91 0.24
436.98 20.00 0.49 14.25 1.15 433.90 26.60 0.61 15.75 0.47 441.28
31.76 0.49 15.76 0.66 435.52 34.84 0.69 16.09 0.53 434.59
Compaction Data For Example 13
[0165] TABLE-US-00038 Compaction Std. dev. Tablet hardness Std.
dev. Avg. Tablet mass force (kN) (kN) (kp) (kp) (mg) 3.97 0.43 3.50
0.78 435.09 7.05 0.83 6.86 0.76 442.75 13.80 1.24 9.76 0.25 438.2
22.56 1.42 9.92 0.45 442.01 25.92 1.29 10.02 0.42 443.17 30.39 0.73
9.79 0.33 436.73 35.28 2.64 10.53 0.26 442.37
Compaction Data For Example 14
[0166] TABLE-US-00039 Compaction Std. dev. Tablet hardness Std.
dev. Avg. Tablet mass force (kN) (kN) (kp) (kp) (mg) 4.98 0.22 5.59
0.79 436.18 8.06 0.82 8.40 0.44 436.08 14.11 0.79 10.15 0.35 437.70
19.92 2.05 10.28 0.42 438.96 26.61 3.22 10.08 0.79 440.82 29.40
0.96 9.77 0.86 436.35 36.21 1.76 9.86 1.04 437.68
Compaction Data For Example H
[0167] TABLE-US-00040 Compaction Std. dev. Tablet hardness Std.
dev. Avg. Tablet mass force (kN) (kN) (kp) (kp) (mg) 4.63 0.24 2.70
0.20 439.39 9.51 0.39 5.67 0.40 437.44 15.02 0.94 9.68 0.50 436.26
20.38 0.47 11.38 0.36 435.15 27.88 0.82 12.05 0.52 435.01 30.17
0.99 12.74 0.31 445.15 36.15 0.59 13.00 0.61 442.29
[0168] FIG. 7 shows a comparison of the compaction characteristics
of i) St. John's Wort extract co-spray dried with 24.9% silicified
MCC and 5.2% silicon dioxide (Example 5), ii) St. John's Wort
extract co-spray dried with 31.7% silicified MCC (Example 4); iii)
St. John's Wort extract which is not co-spray dried with silicified
MCC (Example C); iv) St. John's Wort extract co-spray dried with
25% silicified MCC and no silicon dioxide (Example 11); and v) St.
John's Wort extract co-spray dried with 20% silicified MCC (Example
10); wherein each formulation was blended with 3% Explotab and 0.5%
MgStearate to obtain the mixture of Examples 9-2, 12, H, 13, and 14
respectively, and then tableted.
[0169] As shown in FIG. 7, the formulation of Example 9-2 (co-spray
dried with silicified MCC and silicon dioxide) provided the best
compaction characteristics. The compaction characteristics of the
formulation of Example 12 (co-spray dried with 31% silicified MCC)
were far worse than the formulation of Example 9-2, but still
significantly better than Comparative Example H (not co-spray dried
with silicified MCC). Interestingly, however, the compaction
characteristics of the formulations of Example 13 (co-spray dried
with 25% silicified MCC) and Example 14 (co-spray dried with 20%
silicified MCC) were worse than Examples 9-2 and 12, and were, in
fact, comparable to the formulation of Comparative Example H.
Ginseng Extract Formulations
[0170] FIG. 8 is a graph of moisture uptake for the Ginseng extract
compositions of Examples 2 and B. Twenty-five gram samples of
Examples B and 2 were maintained at 25 C and 40% RH. As shown in
FIG. 8, the ginseng extract that was co-sprayed dried with
silicified MCC (Example 2) absorbed about 40% less moisture over
240 minutes as the ginseng extract which was not co-spray dried
with silicified MCC. However, in view of the fact that the
composition of Example 2 includes 17.5 grams of Ginseng extract
(0.70*25), whereas the composition of Example B includes 24.175 g
of Ginseng extract (0.967*25), a "weight corrected" plot for
Example 2 is also included in FIG. 8. The data for "Example 2 with
Weight Correction" in FIG. 8 was obtained by multiplying each data
point of Example 2 by 24.175/17.5. Based upon the above, the
Ginseng extract that was co-sprayed dried with silicified MCC
(Example 2) has acceptable moisture uptake when compared the St.
John's Wort extract which was not co-spray dried with silicified
MCC (Example B)
[0171] FIG. 9 is a graph of mass flow (g/s) as a function of
aperture size (mm) for the Ginseng composition of Example 2. Flow
data was collected using a Hanson Flodex.TM. (Hanson Research
Instruments, Inc.). Flow data was collected for the composition of
Example 2 and the composition of Example B blended with 30% Prosolv
SMCC 50 (Example J). It should be appreciated that in view of the
fact that the composition of Example B is 96.7% ginseng extract, it
was blended with 30% Prosolv SMCC 50 for purposes of comparison
with Example 2, which contains 70% ginseng extract. The flodex cup
diameter used for each composition was 5.7 cm, each composition had
an initial mass of 95.6 g, and the experiment was conducted at 62%
RH. The flow data for Example 2 is as follows:
Flow Data For Example 2
[0172] TABLE-US-00041 Trial 1 Trial 2 Trial 3 Mass Aperture mass
mass mass flow rate (mm) time (s) (g) time (s) (g) time (s) (g) (g
s-1) 26 2.10 66.50 2.00 61.80 2.20 63.00 30.37 22 2.30 59.90 2.00
55.90 1.90 58.80 28.16 18 3.20 45.30 2.80 48.20 3.30 50.50 15.48 14
6.6 47.6 5.8 47.8 5.3 46.8 8.03 12 8.5 46.9 8.9 41.5 6.5 40.9 5.41
10 14.8 46.1 11.7 41.5 12.7 43.9 3.35 9 12 34.6 15.5 36.9 14.2 40.9
2.70 8 Bridged
[0173] The composition of Example J bridged at 30 mm, and,
therefore, is not shown in FIG. 9. In contrast, the Ginseng
composition of Example 2 bridged at 8 mm. As such, the composition
of Example 2 provides superior flow characteristics as compared
with the composition of Example B even when Example B is blended
with 30% Prosolv SMCC 50 in an attempt to improve its flow
characteristics.
[0174] FIG. 10 is a graph of tablet hardness as a function of
compaction force for the compositions of Examples I and 15. Each
composition was tableted in a caplet shaped 0.750''.times.0.3125'',
and the tablets had a target tablet mass of 800 mg. The compaction
data for each formulation is set forth below:
Compaction Data For Example 15
[0175] TABLE-US-00042 Compaction Tablet hardness force (kN) (kp)
10.4 6.8 15 12.7 20.2 19.8 25.8 26.5
Compaction Data For Example I
[0176] TABLE-US-00043 Compaction Tablet hardness force (kN) (kp)
9.8 14.5 14 23.9 20.9 37.1 23.7 40.2
[0177] As shown in FIG. 10 and the above data, the Ginseng extract
co-spray dried with 25% silicified MCC and 5% colloidal silicon
dioxide (Example 15) exhibits acceptable compaction and hardness
characteristics.
Artichoke Leave Extract Formulations
[0178] FIG. 11 is a graph of mass flow (g/s) as a function of
aperture size (mm) for the Artichoke compositions of Examples 1 and
A. Flow data was collected using a Hanson Flodex.TM. (Hanson
Research Instruments, Inc.). The compositions of Example 1 and
Example A each had an initial mass of 95.6 g. The flodex cup
diameter used for each example was 5.7 cm, and the test was
conducted at 24% RH.
Flow Data For Example 1
[0179] TABLE-US-00044 Trial 1 Trial 2 Trial 3 Mass Aperture time
mass time mass time mass flow rate (mm) (s) (g) (s) (g) (s) (g) (g
s-1) 20 2.80 73.91 2.80 75.67 3.10 78.64 26.23 16 5.80 76.59 4.50
72.49 6.40 74.38 13.38 12 8.60 72.21 9.30 71.58 11.40 75.53 7.49 10
16.40 73.15 15.00 70.72 14.30 70.96 4.70 8 22.60 69.73 21.20 68.40
24.70 74.22 3.10 6 44.20 66.75 44.60 68.45 44.80 66.45 1.51 4
157.00 66.45 111.10 64.40 114.20 65.60 0.51
Flow Data For Example A
[0180] TABLE-US-00045 Trial 1 Trial 2 Trial 3 Mass Aperture time
mass time mass time mass flow rate (mm) (s) (g) (s) (g) (s) (g) (g
s-1) 20 2.10 65.88 3.60 72.54 2.50 68.35 25.22 16 3.20 63.10 3.90
72.14 4.70 68.42 17.26 12 10.30 70.17 8.60 68.23 7.60 64.82 7.67 10
12.70 68.24 13.60 63.55 12.60 64.57 5.05 8 21.20 67.43 21.50 61.73
20.90 63.93 3.04 5 68.00 63.79 71.10 66.95 69.40 64.75 0.94 4
127.00 54.90 114.30 56.83 112.00 56.99 0.48
[0181] As shown in FIG. 11, the Artichoke extract coprocessed with
silicified MCC in accordance with the present invention (Example 1)
exhibits equivalent flow characteristics to the artichoke extract
which is not coprocessed with silicified MCC (Comparative Example
A). It should be noted that equivalent flow characteristics were
obtain despite the fact that the formulation of Example 1 had 70%
artichoke leaves extract as compared to 51.6% artichoke leaves
extract in Example A.
[0182] FIG. 12 is a graph of moisture uptake for artichoke extract.
Twenty-five gram samples of Examples 1 and A were maintained at
25.degree. C. and 40% RH. As shown in FIG. 12, the artichoke
extract that was co-sprayed dried with silicified MCC (Example 1)
absorbed over twice as much moisture over 800 minutes than the
artichoke extract which was not co-spray dried with silicified MCC.
However, despite the fact that the extract of Example 1 absorbed
more moisture than the extract of Example A, both extracts were
able to flow at aperture sizes as small as 4 mm as demonstrated in
FIG. 11.
[0183] FIG. 13 is a graph of tablet hardness as a function of
compaction force for the compositions of Examples 16 and G. Each
composition was tableted in a caplet shaped 0.750''.times.0.3125'',
and the tablets had a target tablet mass of 800 mg. The compaction
data for each formulation is set forth below:
Compaction Data For Example 16
[0184] TABLE-US-00046 Compaction Tablet hardness force (kN) (kp)
10.3 5.4 15.1 10.8 19.8 15.8 24.8 21.7
Compaction Data For Example G
[0185] TABLE-US-00047 Compaction Tablet hardness force (kN) (Kp)
10.3 2.2 15.6 5.01 19.6 8.1 25.1 12.8
[0186] As shown in FIG. 13 and the above data, the artichoke
extract co-spray dried with 25% silicified MCC and 5% colloidal
silicon dioxide exhibits superior compaction and hardness
characteristics, when tableted with talc and sodium stearyl
fumarate (Example 16), than an Artichoke extract that is tableted
in the same manner, but is not co-spray dried with silicified MCC
(Example G).
[0187] As one of ordinary skill in the art will appreciate, the
compaction data set forth above indicates that since the
formulations of Examples 7-9, 12, 15 and 16 exhibit superior
compaction characteristics to comparative examples E, F, H, I, and
K, the formulations in accordance with these examples can be
compressed into smaller tablets than their corresponding
comparative examples. For example, St. John's Wort is currently
marketed in 600 mg capsules, wherein each capsule includes 150 mg.
of St. John's Wort extract. In contrast, as shown in the table
below, with the formulations of Examples 8 and 9-2, 300 mg of St.
John's Wort extract can be included in a 450 mg. tablet
(normalizing the compaction data for these examples to a 450 mg.
tablet): TABLE-US-00048 Actual Amount Normalized Active Actual
Normalized Amount Agent Tablet Tablet Wt. Tablet Active Percent
Active Composition (mg) size (mg) Weight Agent (mg) Agent Example
9-2 297.46993 0.2230'' .times. 0.5670 441 mg 450 303.54 67.4535
Example 8 383.075 0.250'' .times. 0.750'' 550 mg 450 313.425
69.65
[0188] Similarly, Ginseng is currently marketed in 450 mg tablets,
wherein each tablet includes 100 mg. of Ginseng extract. In
contrast, as shown in the table below, with the formulations of
Example 16, 500 mg of Ginseng extract can be included in a 752 mg.
tablet (normalizing the compaction data for this example to a 752
mg. tablet): TABLE-US-00049 Actual Amount Normalized Active Actual
Normalized Amount Agent Tablet Tablet Wt. Tablet Active Percent
Active Composition (mg) size (mg) Weight Agent (mg) Agent Example
16 539.628 0.750'' .times. 0.3125'' 800 752 507.250 67.4535
[0189] In the preceding specification, the invention has been
described with reference to specific exemplary embodiments and
examples thereof. It will, however, be evident that various
modifications and changes may be made thereto without departing
from the broader spirit and scope of the invention as set forth in
the claims that follow. The specification and drawings are
accordingly to be regarded in an illustrative manner rather than a
restrictive sense.
* * * * *