U.S. patent application number 09/881366 was filed with the patent office on 2001-11-22 for novel solid pharmaceutical dispersions.
Invention is credited to Fawzi, Mahdi B., Ghebre-Sellassie, Isaac, Nesbitt, Russell U., Parikh, Riten, Reisch, Robert JR..
Application Number | 20010044409 09/881366 |
Document ID | / |
Family ID | 25201894 |
Filed Date | 2001-11-22 |
United States Patent
Application |
20010044409 |
Kind Code |
A1 |
Ghebre-Sellassie, Isaac ; et
al. |
November 22, 2001 |
Novel solid pharmaceutical dispersions
Abstract
A novel solid pharmaceutical dispersion that improves the
bioavailability of poorly water soluble drugs is produced by
combining the drug with a polymer carrier such as
polyvinylpyrrolidone. The drug is combined with the carrier without
the need for using organic solvents or melting temperatures
(fusion) through the use of a transition compound such as
polyethylene glycol which partially solubilizes the drug and/or
plasticizes the polymer.
Inventors: |
Ghebre-Sellassie, Isaac;
(Morris Plains, NJ) ; Reisch, Robert JR.; (Butler,
NJ) ; Parikh, Riten; (Randolph, NJ) ; Fawzi,
Mahdi B.; (Flanders, NJ) ; Nesbitt, Russell U.;
(Somerville, NJ) |
Correspondence
Address: |
Warner-Lambert Company
2800 Plymouth Road
Ann Arbor
MI
48105
US
|
Family ID: |
25201894 |
Appl. No.: |
09/881366 |
Filed: |
June 14, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09881366 |
Jun 14, 2001 |
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08218495 |
Mar 28, 1994 |
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08218495 |
Mar 28, 1994 |
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07809656 |
Dec 18, 1991 |
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Current U.S.
Class: |
514/26 ; 424/465;
514/179 |
Current CPC
Class: |
A61K 9/1694 20130101;
A61K 9/146 20130101 |
Class at
Publication: |
514/26 ; 424/465;
514/179 |
International
Class: |
A61K 009/20; A61K
031/56 |
Claims
What we claim is:
1. A process for the preparation of a poorly water soluble drug in
solid dispersion comprising a) blending the drug with a carrier; b)
dissolving a surfactant and a plasticizer/solubilizer in water; c)
spraying the surfactant-plasticizer/solubilizer solution onto the
drug/carrier mixture in a fluid bed granulator; d) extruding the
resulting granulation through a twin screw extruder with at least
one heating zone; and, e) milling the extrudate to a powdery mass
of the solid drug dispersion.
2. The process of claim 1 wherein said drug is selected front the
group consisting of acetohexamide, ajamaline, amylobarbitone,
bendrofluozide, benzbromarone, benzonatate, benzylbenzoate,
betamethazone, chloramphenicol, chlorpropamide, chlorthalidone,
clofibrate, corticesteroids, diazepam, dicumerol, digitoxin,
dihydroxypropyltheophyll- ine, ergot alkaloids, ethotoin,
frusemide, glutethimide, griseofulvin, hydrochlorothiazide,
hydrocortisone, hydroflumethiazide, hydroquinone,
hydroxyalkylxanthines, indomethacin, isoxsuprine hydrochloride,
ketoprofen, khellin, meprobamate, nabilone, nicotainamide,
nifedipine, nitrofurantoin, novalgin, nystatin, papaverine,
paracetamol, phenylbutazone, phenobarbitone, prednisolone,
prednisone, primadone, reserpine, romglizone, salicylic acid,
spiranolactone, sulphabenzamide, sulphadiamadine,
sulphamethoxydiazine, sulphamerazine, succinylsulphathiazole,
sulphamethizole, sulphamethoxazole, sulphathiazole, sulphisoxazole,
testosterone, tolazoline, tolbutamide, trifluoperazine,
trimethaprim and mixtures thereof.
3. The process of claim 2 wherein said carrier is selected from the
group consisting of polyvinyl pyrrolidone, high molecular weight
polyethylene glycol, urea, citric acid, vinyl acetate copolymer,
Eudragit.RTM. acrylic polymers, succinic acid, sugars and mixtures
thereof.
4. The process of claim 3 wherein said plasticizer/solubilizer is
selected from the group consisting of low molecular weight
polyethylene glycol, propylene glycol, glycerin, triacetin,
triethyl citrate, sugar alcohols and mixtures thereof.
5. The process of claim 4 wherein said surfactant is selected from
the group consisting of Tween, Span, Pluronics, polyoxyethylene
sorbitol esters, monodiglycerides, polyoxyethylene acid
polyoxyethylene alcohol and mixtures thereof.
6. The process of claim 5 wherein said granulation is extruded at a
temperature less than the decomposition point of said drug.
7. The process of claim 6 wherein said drug and carrier are mixed
in ratios of from about 1:9 to about 5:1 respectively, on a percent
weight basis.
8. The process of claim 7 wherein said drug and carrier are mixed
in a ratio of from about 3:1 to about 1:3 respectively, on a
percent weight basis.
9. A solid pharmaceutical dispersion with improved solubility
characteristics consisting essentially of a poorly water soluble
drug and; a) a carrier selected from the group consisting of
polyvinyl pyrrolidone, high molecular weight polyethylene glycol,
urea, citric acid, Eudragit.RTM. acrylic polymers, succinic acid
and mixtures thereof and, b) a solubilizer/plasticizer selected
from the group consisting of polyols, phthalate esters, glycerol
esters, citrate esters, sugar alcohols and mixtures thereof.
10. The solid pharmaceutical dispersion of claim 9 wherein said
poorly water soluble drug is selected from the group consisting of
acetohexamide, ajamaline, amylobarbitone, bendrofluozide,
benzbromarone, benzonatate, benzylbenzoate, betamethazone,
chloramphenicol, chlorpropamide, chlorthalidone, clofibrate,
corticesteroids, diazepam, dicumerol, digitoxin,
dihydroxypropyltheophylline, ergot alkaloids, ethotoin, frusemide,
glutethimide, griseofulvin, hydrochlorothiazide, hydrocortisone,
hydroflumethiazide, hydroquinone, hydroxyalkylxanthines,
indomethacin, isoxsuprine hydrochloride, ketoprofen, khellin,
meprobamate, nabilone, nicotainamide, nifedipine, nitrofurantoin,
novalgin, nystatin, papaverine, paracetamol, phenylbutazone,
phenobarbitone, prednisolone, prednisone, primadone, reserpine,
romglizone, salicylic acid, spiranolactone, sulphabenzamide,
sulphadiamadine, sulphamethoxydiazine, sulphamerazine,
succinylculphathiazole, sulphamethizole, sulphamethoxazole,
sulphathiazole, sulphisoxazole, testosterone, tolazoline,
tolbutamide, trifluoperazine, trimethaprim and mixtures
thereof.
11. The solid pharmaceutical dispersion of claim 10 wherein said
drug and carrier are formulated in ratios of from about 1:9 to
about 5:1 respectively, on a percentage weight basis.
12. The solid pharmaceutical dispersion of claim 11 wherein said
drug and said carrier are formulated in ratios of from about 3:1 to
about 1:3, respectively on a percentage weight basis.
13. A solid pharmaceutical dispersion with improved solubility
characteristics comprised of a poorly water soluble drug and a
carrier produced by the process consisting of: a) mixing said drug
and the carrier in a ratio of approximately 1:9 to about 5:1
respectively, on a percent weight basis; b) spraying onto said
mixture a solution consisting of a plasticizer/solubilizer, and
optionally, a surfactant; c) extruding the resultant granulation in
a twin screw extruder with at least one heating zone; and d)
milling the extrudate to a powdery mass.
14. The solid pharmaceutical dispersion of claim 13 wherein said
drug is selected from the group consisting of acetohexamide,
ajamaline, amylobarbitone, bendrofluozide, benzbromarone,
benzonatate, benzylbenzoate, betamethazone, chloramphenicol,
chlorpropamide, chlorthalidone, clofibrate, corticesteroids,
diazepam, dicumerol, digitoxin, dihydroxypropyltheophylline, ergot
alkaloids, ethotoin, frusemide, glutethimide, griseofulvin,
hydrochlorothiazide, hydrocortisone, hydroflumethiazide,
hydroquinone, hydroxyalkylxanthines, indomethacin, isoxsuprine
hydrochloride, ketoprofen, khellin, meprobamate, nabilone,
nicotainamide, nifedipine, nitrofurantoin, novalgin, nystatin,
papaverine, paracetamol, phenylbutazone, phenobarbitone,
prednisolone, prednisone, primadone, reserpine, romglizone,
salicylic acid, spiranolactone, sulphabenzamide, sulphadiamadine,
sulphamethoxydiazine, sulphamerazine, succinylsulphathiazole,
sulphamethizole, sulphamethoxazole, sulphathiazole, sulphisoxazole,
testosterone, tolazoline, tolbutamide, trifluoperazine,
trimethaprim and mixtures thereof.
15. The solid pharmaceutical dispersion of claim 14 wherein said
carrier is selected from the group consisting of polyvinyl
pyrrolidone, high molecular weight polyethylene glycol, urea,
citric acid, vinyl acetate copolymer, Eudragit.RTM. acrylic
polymers, succinic acid, sugars and mixtures thereof.
16. The solid pharmaceutical disperson of claim 15 wherein said
plasticizer/solubilizer is selected from the group consisting of
low molecular weight polyethylene glycol, propylene glycol,
glycerin, triacetin, triethyl citrate, sugar alcohols and mixtures
thereof.
17. The solid pharmaceutical dispersion of claim 16 wherein said
surfactant is selected from the group consisting of Tween, Span,
Pluronics, polyoxyethylene sorbitol esters, polyoxyethylene acid,
polyoxyethylene alcohols and mixtures thereof.
18. The solid pharmaceutical dispersion of claim 17 wherein said
extrusion is carried out at a temperature below the decomposition
point of said drug.
19. The solid pharmaceutical dispersion of claim 18 wherein said
extrusion occurs at a rate of approximately 2 gm/sec. to about 7
gm/sec.
Description
BACKGROUND OF THE INVENTION
[0001] The bioavailabilities of many poorly water soluble drug
entities are limited by their dissolution rates which in turn are
governed by the particle size and hence the specific surface area
and/or the polymorphic state of the active ingredient. At times,
these problems are overcome by particle size reduction. There are
cases, however, where the dissolution rates of the drug are not
favorable enough to improve its bioavailability. Therefore,
techniques such as lyophilization, solvent deposition, solvate
formation and solid dispersion have been employed to improve the
absorption of drugs.
[0002] A solid dispersion is a pharmaceutical formulation which may
be defined as "a dispersion of one or more active ingredients in an
inert carrier or matrix at solid state prepared by melting the two
(fusion), dissolving them in a solvent, or a combination of
approaches, i.e., a quasi melting-solvent method". The
solvent-based process uses organic solvents to dissolve and
intimately disperse the drug and carrier molecules. The process is
relatively difficult. Identification of a common solvent for both
drug and carrier is a tedious exercise, and complete solvent
removal from the product is, if at all possible, a lengthy process.
In addition, the volume of solvents required is excessive, and the
cost of solvent recovery systems is prohibitive. The drug and
carrier are dissolved in a solvent such as methylene chloride,
acetone, ethanol and mixtures thereof and the solvent is later
removed by evaporation or the like while the drug/carrier solid
dispersion is collected as a powdered mass. Not only is the process
lengthy and expensive, but the use of organic solvents renders it
hazardous and toxic as well.
[0003] The second process for the manufacture of pharmaceutical
dispersions involves fusion of the two components where the drug
and the carrier are allowed to melt at temperatures at or above the
melting point of the drug. In the fusion process, the drug and
carrier are first blended and melted in a suitable mixer. The
molten mixture is then cooled rapidly to provide a congealed mass
which is subsequently milled to produce a powder. The fusion
process is technically simple provided that the drug and carrier
are miscible in the molten state but this is not always the case
and furthermore, the process is limited in that it tends to lead to
drug decomposition due to the high temperatures required to melt
the two components.
[0004] A third method that is used to produce a solid dispersion
when there is difficulty with thermal instability and immiscibility
between the drug and the carrier is the hybrid fusion-solvent
method. The drug is first dissolved in a small quantity of organic
solvent and added to the molten carrier. The solvent is then
evaporated to generate a product that is subsequently, milled to
produce a powder. The pharmacokinetics, dissolution rates and
processes for formulation of many different solid pharmaceutical
dispersions is discussed at length in an article by Ford, J., in
Pharm. Acta. Helv. 61, 3; 69-88 (1986).
[0005] It is an object of the present invention to describe a novel
manufacturing process for a solid pharmaceutical dispersion which
obviates the need for organic solvents, elevated melting
temperatures or the use of both. In particular, it is an object of
the present invention to produce a solid pharmaceutical dispersion
by incorporating in the formulation a solubilizer/plasticizer which
acts as a vehicle to reduce the transition temperature by partially
solubilizing the drug and/or plasticizing the polymer. This is
particularly useful in the formulation of solid pharmaceutical
dispersions for drugs that decompose at or near their melting
temperatures.
[0006] U.S. Pat. No. 4,803,081 to Falk et al. discloses an extended
release preparation of an active compound with very low solubility
wherein the compound is dispersed in a liquid or semi-solid
non-ionic solubilizer such as esters and ethers of polyethylene
glycols. The solubilized drug is then combined with a hydrophilic
gel system which controls the release of the drug and solubilizer
at a constant even rate.
[0007] U.S. Pat. No. 4,689,235, to Barnes et al. discloses an
extrudable encapsulation matrix which improves the loading capacity
for oils, flavors, pharmaceuticals and the like. The matrix is
comprised of maltodextrin and hydrogen octenylbutanedioate
amylodextrin or its equivalent. The formulation improves the
extrusion processability of the drug and enables high levels of
active agent to be incorporated into the dosage form.
[0008] U.S. Pat. No. 4,678,516 to Alderman et al. teaches the
formation of sustained release dosage forms utilizing a gel matrix
comprised of hydroxypropyl methyl cellulose (HPMC) and a major
amount of a plasticizer in which the active pharmaceutical is
dispersed. Suitable plasticizers include low molecular weight
polyols such as ethylene glycol, propylene glycol, polyethylene
glycol and the like. The plasticizer is employed to render the
matrix thermoformable and comprises a major amount thereof, i.e.,
at least 30%. The active agent must be heat stable however, so that
it is capable of being heated to a temperature sufficient to
prepare a gel matrix from the HPMC and the plasticizer without
being rendered inactive.
[0009] PCT Appln. No. WO 83/00091 teaches the formulation of a
polymeric diffusion matrix for the sustained release of water
insoluble cardiovascular drugs such as 5-[(3,4-dimethoxyphenyl
ethyl)methylamino]-2-(3,4 dimethoxyphenyl)-2-isopropyl
valeronitirile. The matrix is comprised of a polar plasticizer,
polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) in ratios of
about 2:1:1 respectively. The cardiovascular pharmaceutical matrix
is particularly useful in transdermal formulations wherein the drug
is delivered at a constant sustained rate across the skin.
[0010] The present invention does away with the need for elaborate
chemical matrices and increases the bioavailability of water
insoluble drugs through the formation of a solid pharmaceutical
dispersion. The dispersion is formulated without the need of using
organic solvents or melting temperatures of drugs (fusion) which
would otherwise decompose many drugs which do so at or near their
melting temperature.
SUMMARY OF THE INVENTION
[0011] The present invention is a novel pharmaceutical solid
dispersion and the process for its preparation whereby generally
water insoluble drugs are combined with a carrier polymer such as
polyvinyl pyrrolidone (PVP) without the need for organic solvents
and/or high fusion temperatures. The process utilizes a vehicle
such as polyethylene glycol which reduces the transition
temperature and facilitates the molecular interaction between the
drug and a polymer such as polyvinyl pyrrolidone (PVP) by partially
solubilizing the drug and/or plasticizing the polymer. This allows
for a continuous and well controlled processing mode of
manufacture.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The solid pharmaceutical dispersions of the present
invention increase the bioavailability of various water insoluble
drugs by increasing their dissolution rates which in turn produce
increases in both the rates and extent of the drugs absorption.
Hence, the dosage of many solid dispersed drugs can be decreased
and it is also believed that due to the increased dissolution and
associated rapid absorption may reduce the proportion of the drug
that is metabolized presystematically.
[0013] Nearly any water-insoluble drug may be formulated in the
practice of the present invention so as to increase its solubility
and hence its bioavailability. Drugs that are particularly useful
in the practice of the present invention are those that decompose
at or near their melting temperature since these certainly cannot
be formulated into solid pharmaceutical dispersions using the
fusion method. Suitable pharmaceuticals include, but are not
limited to acetohexamide, ajamaline, amylobarbitone,
bendrofluozide, benzbromarone, benzonatate, benzylbenzoate,
betamethasone, chloramphenicol, chlorpropamide, chlorthalidone,
clofibrate, corticesteroids, diazepam, dicumerol, digitoxin,
dihydroxypropyltheophylline, ergot alkaloids, ethotoin, frusemide,
glutethimide, griseofulvin, hydrochlorothiazide, hydrocortisone,
hydroflumethiazide, hydroquinone, hydroxyalkylxanthines,
indomethacin, isoxsuprine hydrochloride, ketoprofen, khellin,
meprobamate, nabilone, nicotainamide, nifedipine, nitrofurantoin,
novalgin, nystatin, papaverine, paracetamol, phenylbutazone,
phenobarbitone, prednisolone, prednisone, primadone, reserpine,
romglizone, salicylic acid, spiranolactone, sulphabenzamide,
sulphadiamadine, sulphamethoxydiazine, sulphamerazine,
succinylsulphathiazole, sulphamethizole, sulphamethoxazole,
sulphathiazole, sulphisoxazole, testosterone, tolazoline,
tolbutamide, trifluoperazine, trimethaprim and other water
insoluble drugs.
[0014] Suitable carrier polymers that are useful in the formation
of the solid drug dispersion include, but are not limited to,
polyvinylpyrrolidone (PVP), high molecular weight polyethylene
glycol (PEG), urea, citric acid, vinyl acetate copolymer,
Eudragit.RTM. acrylic polymers, succinic acid, sugars and mixtures
thereof. The carrier of choice obviously is dependent upon the drug
to be dispersed but generally the chosen carrier must be
pharmacologically inert and chemically compatible with the drug in
the solid state. They should not form highly bonded complexes with
a strong association constant and most importantly should be freely
water soluble with intrinsic rapid dissolution properties.
[0015] Preferably, the carrier of choice in most dispersions is
polyvinylpyrrolidone (PVP) which is a polymer of the monomeric unit
(C.sub.6H.sub.9NO).sub.n and is a free flowing amorphous powder
that is soluble in both water and organic solvents. It is
hygroscopic in nature and compatible with a wide range of
hydrophilic and hydrophobic resins. Another preferred carrier is a
high molecular weight polyethylene glycol such as (PEG) 6000 which
is a condensation polymer of ethylene glycol with the general
formula (HOCH.sub.2(CH.sub.2OCH.sub.2)).sub.nCH.sub.2OH.
Polyethylene glycols are generally a clear, colorless, odorless
viscous liquid to waxy solid that is soluble or miscible with
water.
[0016] The surprising and unexpected results of the present
invention is the creation of a solid pharmaceutical dispersion
comprised of the aforementioned water insoluble drugs and carriers
without the need for using organic solvents, fusion (heat) or both
(solvent/heat) which are either lengthy and expensive methods or
which limit the types of drugs that can be formulated, i.e. heat
labile drugs. Surprisingly, it was discovered that the addition of
a plasticizer/solubilizer during the mixing of the two components
results in a chemical environment that readily lends itself to
dispersion formation.
[0017] Suitable plasticizers/solubilizers useful in the practice of
the present invention include low molecular weight polyethylene
glycols such as PEG 200, PEG 300, PEG 400 and PEG 600. Other
suitable plasticizers include propylene glycol, glycerin,
triacetin, triethyl citrate, and sugar alcohols such as sorbitol,
mannitol, and mixtures thereof. Optionally, a surfactant such as
Tween 80 may be added to facilitate wettability within the
formulation.
[0018] The water insoluble drug of interest is first blended with
the carrier using any appropriate mixer in a drug/carrier ratio of
from about 1:9 to about 5:1 respectively, based upon a percentage
weight basis. Preferably, the drug/carrier ratio will be
approximately 3:1 to about 1:3, respectively. The blend is then
transferred to a fluid bed granulator and a plasticizer such as PEG
400 is dissolved in water with a surfactant such as Tween 80, if
necessary. Other suitable surfactants include Tweens 20 and 60,
Span 20, Span 40, Pluronics, polyoxyethylene sorbitol esters,
nionoglycerides, polyoxyethylene acids, polyoxyethylene alcohols
and mixtures thereof. Once both ingredients are sufficiently
dissolved, the solution is sprayed onto the powder blend in the
fluid bed granulator under specific conditions. The resultant
granulation is transferred to a container and fed into a high
intensity mixer such as a twin screw extruder with at least one,
and preferably more than one heating zones. The mixture is then
extruded at appropriate temperatures depending on the heat
stability of the drug until a solid dispersion is collected as an
extrudate which is then transferred to a drum for milling. The
solid pharmaceutical dispersion is then ground into a powdery mass
and further prepared in a tablet or capsule form which may be
optionally coated with a film such as hydroxypropyl methyl
cellulose if desired.
[0019] The following examples are given to more particularly set
forth and teach several specifics of the present invention. It must
be remembered that they are for illustrative purposes only and
should not be construed in a manner that will limit the spirit and
scope of the invention as recited by the claims that follow:
EXAMPLE 1
[0020] Romglizone, whose chemical name is
(+)-5-[4-(6-hydroxy-2,5,7,8-tetr-
amethylchroman-2-ylmethoxy)-benzyl]-2,4-thiazolidinedione, is a
novel insulin-sensitizing drug being developed for the treatment of
non-insulin-dependent diabetes mellitus. The chemical structure of
the drug is as follows: 1
[0021] The drug is practically insoluble in water. Its solubility
slightly increases as the pH of the aqueous media increases. In
vivo studies involving animal models showed that the drug has poor
bioavailability when administered in its original crystalline form.
In contrast, when an equivalent solid dispersion of the drug in
polyvinylpyrrolidone (PVP) was given, the bioavailability of the
drug improved significantly.
[0022] Romglizone (500 gm.) and polyvinylpyrrolidone (PVP) (300
gm.) were blended in P-K blender (Make, Model) for eight (8)
minutes and subsequently transferred to a fluid bed granulator.
Simultaneously, a surfactant such as Tween 80 (30 gm.) was
dissolved with polyethylene glycol 400 (75 gm.) in a sufficient
amount of water for complete dissolution. The Tween/PEG/H.sub.2O
solution was then sprayed onto the drug/PVP blend in a Roto-Glatt
GPCG-5 fluid bed granulator at 36-40.degree. C. until the solution
is exhausted. The resultant granulation was then fed into a twin
screw extruder with four heating zones set at 125.degree. C.,
125.degree. C., 125.degree. C. and 115.degree. C. respectively. The
solid dispersion is extruded at a rate of five gms/sec at a head
pressure no greater than 5,000 p.s.i. and collected in a drum
containing a dessicant such as selica gel. The collected extrudate
was then milled using a standard mill such as a Fitzmill to produce
a fine powdery mass of the Romglizone solid dispersion.
EXAMPLE II
[0023] A batch of solid pharmaceutical dispersion comprising
Romglizone was made according to the procedure set forth in Example
I using the following materials and proportions. Values given refer
to the amount of ingredients in a single tablet.
1 Romglizone 200.00 mg Polyvinylpyrrolidone 120.00 mg Tween 80 NF
12.00 mg Polyethylene glycol 400 NF 30.00 mg Purified H.sub.2O USP
42.60 mg
EXAMPLE III
[0024] The solid phamaceutical dispersion of Example II was further
processed into a tablet core by first thoroughly mixing
approximately 362.0 gm. of the milled material with 10.00 mg. of
Cab-O-Sil. The resultant mixture was then discharged into a P-K
blender and the following materials were then added.
2 Talc USP 4.00 mg. Microcystalline Cellulose NE 29.00 mg. Low
substituted Hydroxypropyl 120.00 mg. Cellulose (L-HPC)
[0025] The materials were tumble blended for approximately ten (10)
minutes after which a portion of the blend was discharged into a
plastic bag. Magnesium stearate (5.00) gm. was added to the
contents of the bag and the ingredients were mixed well. The mix
was then passed through a No. 30 U.S. standard mesh screen, and
added to the main blend. The mixture was again tumble-blended for
an additional three minutes. The final blend was then compressed
into tablet form using a standard capsule-shaped plain punch known
in the art. The tabletted solid dispersion may then be optionally
film coated with hydroxypropyl methylcellulose using a standard pan
coating apparatus.
* * * * *