U.S. patent number 3,907,983 [Application Number 05/438,135] was granted by the patent office on 1975-09-23 for pharmaceutical preparations.
This patent grant is currently assigned to Hoffmann-La Roche Inc.. Invention is credited to Pyare Lal Seth.
United States Patent |
3,907,983 |
Seth |
September 23, 1975 |
Pharmaceutical preparations
Abstract
Powders, the individual particles thereof coated with from about
0.5% to 10% by weight of a material which makes the powder
nydrophilic, and which are free flowing as well as amenable to
tabletting by direct compression are disclosed as well as a method
for making such powders and tablets.
Inventors: |
Seth; Pyare Lal (Arlesheim,
CH) |
Assignee: |
Hoffmann-La Roche Inc. (Nutley,
NJ)
|
Family
ID: |
4231310 |
Appl.
No.: |
05/438,135 |
Filed: |
January 30, 1974 |
Foreign Application Priority Data
|
|
|
|
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Feb 16, 1973 [CH] |
|
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2331/73 |
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Current U.S.
Class: |
424/494 |
Current CPC
Class: |
A61K
9/5047 (20130101); A61K 9/2095 (20130101); A61K
9/1676 (20130101) |
Current International
Class: |
A61K
9/16 (20060101); A61K 9/20 (20060101); A61K
9/50 (20060101); A61J 003/02 () |
Field of
Search: |
;424/35 |
Foreign Patent Documents
Other References
Davies et al., J. Pharm. Sci. 61(4): 618-622 April 1972, "Batch
Production of Pharmaceutical Granulations in a Fluidized Bed II.
Effects of Various Binders and their Concentrations on Granulations
and Compressed Tablets.".
|
Primary Examiner: Rose; Shep K.
Attorney, Agent or Firm: Welt; Samuel L. Saxe; Jon S. Rosen;
Gerald S.
Claims
I claim:
1. A free-flowing water wettable powder which is directly
compressible without prior granulation into rapidly absorbed
tablets and which is composed of individual rapidly disintegrating
particles of a pharmaceutically active substance spray-coated from
aqueous solutions with from about 0.5% to about 10% by weight of a
hydrophilising material selected from the group consisting of
methylcellulose, hydroxyethylmethylcellulose and
hydroxypropylmethylcellulose.
2. The powder of claim 1 wherein the hydrophilising material is
hydroxypropyl methyl cellulose.
3. The powder of claim 1 wherein the active substance is coated
with about 1% to about 5% by weight of a hydrophilising material
selected from the group consisting of methylcellulose,
hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.
4. The powder of claim 1 wherein the active substance is coated
with about 2% to about 3% by weight of a hydrophilising material
selected from the group consisting of methylcellulose,
hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.
5. The powder of claim 1 wherein the individual particles thereof
are composed of a mixture of pharmaceutically active substances,
each of which is coated with a hydrophilising material selected
from the group consisting of methylcellulose,
hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.
6. The powder of claim 1 wherein the individual particles thereof
are composed of a mixture of a pharmaceutically active substance
and pharmaceutically acceptable tabletting adjuvants and
excipients, each of which is coated with a hydrophilising material
selected from the group consisting of methylcellulose,
hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.
7. The powder of claim 3 wherein the hydrophilising material is
hydroxypropylmethyl-cellulose.
8. The powder of claim 1 wherein the active substance is
sulfamethoxazole.
9. The powder of claim 1 wherein the active substance is a mixture
of sulfamethoxazole and trimethoprim.
10. The powder of claim 6 composed of
5-(6-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one
and lactose.
Description
BACKGROUND OF THE INVENTION
Many pharmaceutically active substances, e.g. medicines, vitamins,
are administered in the form of tablets. These tablets are usually
manufactured by first forming granules from powders of the
pharmaceutically active substance. The granules are prepared by
either wet or dry granulation. After the addition of the usual
carriers and/or excipients, the granules are pressed into tablets.
Since it is desirable for the pharmaceutically active substances
contained in the tablets to be rapidly absorbed by the body, it is
desirable for the tablets to disintegrate in an aqueous medium into
particles of the smallest possible size. In order to obtain
greatest benefit from the active substance, the particles should
either dissolve rapidly or be sufficiently wettable to be easily
absorbed. In tablets which are manufactured by compression of
granules, this does not generally occur since such tablets usually
disintegrate initially into the granulate which then disintegrates,
often very slowly, into the smaller particles. Since the individual
particles of the pharmaceutically active substance are, in many
cases poorly wettable, the complete dissolution of the tablets or
the pharmaceutically active substances is considerably delayed and
in some cases never occurs.
DESCRIPTION OF THE INVENTION
By means of the present invention the foregoing disadvantages
inherent in tablets formed from conventionally produced
granulations can be avoided by coating the surface of the
individual particles of the pharmaceutically active substance with
a film of a hydrophilising material, i.e., a material which renders
the particles water-wettable. In this manner a powder having
advantageous properties is formed since such a powder is very
rapidly water-wettable and in many cases is soluble because of the
film of the hydrophilising material. Such a powder is also
advantageous because it is free-flowing and is directly
compressible to tablets without prior granulation procedures. This
is advantageous since, upon dissolution, such tablets disintegrate
directly into the individual pharmaceutically active material
particles and do not disintegrate in two steps as mentioned above
i.e. into the granulate which, in turn, disintegrated into the
individual particles. Because of their free-flowing properties the
powders of this invention can also be readily incorporated into
capsules.
Thus, the present invention in one aspect is concerned with powders
of pharmaceutically active substances in which the surface of the
individual particles of the active substance is coated with a film
of a hydrophilising material, as well as with a process for their
manufacture. The powders are water-wettable, free flowing and
directly compressible into tablets.
The invention is also concerned with pharmaceutical preparations in
a powdered form or in the form of tablets containing at least one
pharmaceutically active substance in combination with conventional
pharmaceutically acceptable tabletting adjuvants and/or excipients.
The active substance or mixtures of active substances and, if
necessary, the conventional carriers and/or excipients are present
in the form of individual particles the surface of which is covered
with a film of a hydrophilising material. Suitable pharmaceutically
acceptable tabletting adjuvants and excipients are
micro-crystalline cellulose, dextrose, lactose, sucrose, mannitol,
glucose, sorbitol; lubricants such as calcium stearate, stearic
acid or magnesium stearate as well as mixtures thereof. Talc,
cornstarch etc. can be mixed with the lubricants. Flavoring agents
and coloring agents can also be used.
The coating of the surface of the individual particles can be
carried out by spraying the particles with a solution of a
hydrophilising material and subsequently drying the product. This
can also be accomplished by suspending the particles in a solution
of a hydrophilising material and subsequently drying the
product.
The amount of hydrophilising material which must be applied to the
surface of the particles in order to produce the desired effect
depends largely on the nature of the particles to be hydrophilised
as well as on the hydrophilising material. Generally, a sufficient
amount should be present to insure that the particles are made
sufficiently waterwettable so tablets made therefrom disintegrate
at the desired rate and in the desired manner. The amount required
generally lies in the range of about 0.5 and 10% by weight based on
the weight of the particles preferably between about 1 and 5% by
weight and most preferred at about 2 to 3% by weight. The amount
required to meet the criteria desired can be determined by means of
the following wettability test. In this test, a known amount of dry
hydrophilised powder is poured on to the surface of the water
contained in a glass beaker and the time required by the powder
layer to become wetted and sink into the water is observed. The
wetting or sinking rate is classified into the following
categories: (a) excellent, (b) good, (c) adequate, (d) poor, (e)
inadequate. The amount of hydrophilising material required in each
individual case can be readily determined according to the
foregoing classification.
Examples of suitable hydrophilising materials which can be used in
the present invention are, for example, the following:
polyvinylpyrrolidone (m.w. 15000-35000), cold-swellable and
water-soluble starches, certain mucins such as gum arabic and the
like in combination with wetting agents as well as water-soluble,
pharmaceutical grade and low viscosity grade (i.e. from about 2 to
about 15 cps) cellulose derivatives, especially methylcellulose or
hydroxyethylmethylcellulose, hydroxypropylmethylcellulose and the
like. A preferred hydrophilising material is a
hydroxypropylmethylcellulose which is commercially available under
the trade name "Pharmacoat 603" (Shinetzu Chemical Company, Tokyo).
This cellulose derivative dissolves well in water and is also
soluble in diverse organic solvents such as isopropanol, methylene
chloride and the like. Furthermore, it has the advantage of an
extremely low viscosity as a result of which relatively
concentrated solutions possess good spraying characteristics.
Suitable solvents for the spraying of the hydrophilising material
are especially those solvents in which the pharmaceutically active
material to be hydrophilised is poorly soluble or insoluble. Since
water fits these criteria it is the preferred solvent. The amount
of hydrophilising material in the solution to be sprayed can vary
but generally lies at between about 2-15% (weight/volume),
preferably at between about 3-10% (weight/volume) and most
preferably at between about 5-10% (weight/volume). Of the useful
compositions the 5-10% (weight/volume) aqueous solutions of
Pharmacoat 603 are especially preferred.
The procedure by which the hydrophilising material is applied to
the surface of the individual particles must be carried out in a
manner which insures that the particles do not become agglomerated.
Except for this limitation any method which provides for the
coating of one substance using a solution of another substance can
be used.
In accordance with the present invention it has been found that
both the coating-drum method and the fluidized-bed method are
especially suitable.
According to the coating-drum method, the particles to be
hydrophilised are maintained in motion in a coating-drum by the
rotation thereof. A solution of the hydrophilising material in a
suitable solvent is then slowly and continuously sprayed into the
drum. During this procedure, care must be taken that the particles
to be coated do not become too damp since they would agglomerate
and form a granulate. The coated particles can be subsequently
dried in the drum or, in the case of large batches, transferred to
a fluidized-bed drier and dried therein.
According to the fluidized-bed method, the particles to be
hydrophilised are placed in a fluidized-bed drier and maintained in
motion by means of air, the input and output temperature of which
is adjusted according to the solvent used. A solution of the
hydrophilising material in a suitable solvent is continuously
sprayed into the drier at a rate which ensures that the particles
to be coated do not become too damp and conglomerate. This avoids
formation of a granulate. After completion of the spraying, the
coated particles can be dried directly by a further input of
suitably pre-warmed air.
The individual particles coated with a hydrophilising material
according to the previous methods form a powder which is free
flowing and is directly compressible to tablets without prior
granulation or other pre-treatment.
Individual particles of all poorly wettable or water-insoluble
pharmaceutically active substances can be coated with a
hydrophilising material in accordance with the present invention.
This invention is particularly applicable to those pharmaceutically
active substances which are administered in the form of tablets but
is not limited thereto. Examples of such pharmaceutically active
substances amenable to treatment according to this invention are
sulfamethoxazole, trimethoprim, phenacetin, acetylsalicylic acid,
benzodiazepines and the like.
The powders of the present invention consist of individual
particles each of which is individually coated with a film of a
hydrophilising material. These powders can be directly compressed
to tablets either as formed or after mixing with conventional
pharmaceutically acceptable tabletting carriers and/or excipients.
The powders can also be incorporated into capsules.
The following Examples illustrate the present invention:
EXAMPLE 1
10 g of Pharmacoat 603 dissolved in 90 g of water are continuously
sprayed by means of a spray-gun for a period of 20 minutes into a
constant speed slowly rotating coating-drum of 400 mm diameter
containing 500 g of sulfamethoxazole. The entire coating solution
is sprayed into the drum which is left to rotate for 3 more hours
by which time the contents are completely dry. There is thus
obtained a powder composed of individual particles of
sulfamethoxazole which are free-flowing, directly compressible to
tablets and coated with about 2% by weight of Pharmacoat 603.
In place of 90 grams of water, there can be used with equivalent
results 45 grams of water and 45 grams of ethanol or
isopropanol.
EXAMPLE 2
300 g of Pharmacoat 603 dissolved in 2.7 liters of water are
continuously sprayed by means of a spray-gun for 20 minutes into a
constant speed slowly rotating coating-drum of 120 cm diameter
containing 15 kg of sulfamethoxazole. The entire coating solution
is sprayed into the drum which is left to rotate for 5 more
minutes. Subsequently, the resulting slightly damp material is
removed from the drum, sieved through a 0.5 mm sieve and dried for
0.5 hour in a fluidized-bed drier with an input temperature of
50.degree.C. There is thus obtained a powder composed of individual
particles of sulfamethoxazole which are free-flowing, directly
compressible to tablets and coated with about 2% by weight of
Pharmacoat 603.
In place of 2.7 liters of water there can be used with equivalent
results an equal weight of a 1:1 (wt/wt) mixture of water and
either ethanol or isopropanol.
EXAMPLE 3
15 kg of sulfamethoxazole are sieved through a 0.5 mm sieve and the
powder obtained is added to a fluidized-bed drier having an input
air temperature of 60.degree.C. The air is blown through the powder
continuously until the temperature of the output air has reached
37.degree.C. A 7.5% (weight/volume) aqueous solution of Pharmacoat
603 is then sprayed into the fluidized-bed drier at a rate such
that a total amount of 4 kg of solution is sprayed during a period
of 20 minutes. This causes the temperature of the output air to
decrease to 26.degree.C. and then remain constant. After completion
of the spraying, the material is dried for 15 minutes more in the
apparatus, causing the temperature of the output air to rise to
30.degree.C. There is thus obtained a powder composed of individual
particles of sulfamethoxazole which are free-flowing, directly
compressible to tablets and which are coated with about 2% by
weight of Pharmacoat 603.
EXAMPLE 4
In a manner analogous to that described in Example 1, Example 2 or
Example 3, a powder composed of individual particles of
trimethoprim which are free-flowing, directly compressible to
tablets and coated with about 2% by weight of Pharmacoat 603.
EXAMPLE 5
A mixture of 16 kg of sulfamethoxazole and 3.2 kg of trimethoprim
can be treated in a manner analogous to that described in Example 3
to give a powder whose individual particles of trimethoprim and
sulfamethoxazole are coated with about 2% by weight of Pharmacoat
603 and which can be compressed directly into tablets after
admixture with the usual tabletting adjuvants and excipients.
EXAMPLE 6
20 g of finely powdered
5-(6-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one
are suspended in a 5% aqueous solution of Pharmacoat 603 (prepared
from 20 g of Pharmacoat 603 and 380 ml of water). The aqueous
suspension is then sprayed, by means of a spray-gun, onto 1 kg of
lactose in a rotating coating-drum. The suspension is sprayed in
such a manner that the lactose particles are uniformly coated and
do not become too damp. The resulting product is dried at
40.degree.C. to give a free-flowing powder of a mixture of lactose
particles and
5-(6-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one
particles each coated with about 2% by weight of Pharmacoat 603.
The powder is water-wettable and can be compressed directly into
tablets or incorporated into capsules.
In place of 380 ml of water there can be used with equivalent
results 190 grams water and 190 grams ethanol or isopropanol.
* * * * *