U.S. patent application number 10/635710 was filed with the patent office on 2004-02-12 for process for preparing solid dosage forms for unpalatable pharmaceuticals.
This patent application is currently assigned to Lipton, Division of Conopco, Inc.. Invention is credited to Kearney, Patrick, Thompson, Andrew R., Yarwood, Richard J..
Application Number | 20040028730 10/635710 |
Document ID | / |
Family ID | 26701394 |
Filed Date | 2004-02-12 |
United States Patent
Application |
20040028730 |
Kind Code |
A1 |
Yarwood, Richard J. ; et
al. |
February 12, 2004 |
Process for preparing solid dosage forms for unpalatable
pharmaceuticals
Abstract
A process for the preparation of a rapidly disintegrating dosage
form a pharmaceutically active substance which has an unacceptable
taste wherein there is formed a solution or a suspension in a
solvent of a form of the pharmaceutically active substance which is
less soluble in water and more palatable than the form with the
unacceptable taste together with a water-soluble or
water-dispersible carrier material. Discrete units of the
suspension or solution are formed and the solvent is removed from
the discrete units under conditions whereby a network of the
carrier material carrying a dosage for the less soluble and more
palatable form of the pharmaceutically active substance is
formed.
Inventors: |
Yarwood, Richard J.;
(Collingbourne Kingston, GB) ; Kearney, Patrick;
(Swindon, GB) ; Thompson, Andrew R.; (Swindon,
GB) |
Correspondence
Address: |
Donald O. Nickey
Cardinal Health, Inc.
7000 Cardinal Place
Dublin
OH
43017
US
|
Assignee: |
Lipton, Division of Conopco,
Inc.
|
Family ID: |
26701394 |
Appl. No.: |
10/635710 |
Filed: |
August 5, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10635710 |
Aug 5, 2003 |
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09551361 |
Apr 18, 2000 |
|
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09551361 |
Apr 18, 2000 |
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09026561 |
Feb 20, 1998 |
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09026561 |
Feb 20, 1998 |
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08330936 |
Oct 28, 1994 |
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5738875 |
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Current U.S.
Class: |
424/465 ;
264/109 |
Current CPC
Class: |
A61K 31/454
20130101 |
Class at
Publication: |
424/465 ;
264/109 |
International
Class: |
A61K 009/20; B27N
003/00 |
Claims
We claim:
1. A process for the preparation of a solid, oral, rapidly
disintegrating dosage form of a pharmaceutically active substance
which has an unacceptable taste, which process comprises: a)
forming a system selected from the group consisting of a solution
and a suspension in an aqueous or alcoholic solvent of a form of
the pharmaceutically active substance which is rendered less
soluble in the presence of a carrier material selected from the
group consisting of water-soluble and water-dispersible carrier
materials b) forming discrete units of the system; and c) removing
the solvent from the discrete units under conditions whereby a
network of the carrier material carrying a dosage form the less
soluble and more palatable form of the pharmaceutically active
substance is formed.
2. The process according to claim 1 wherein the pharmaceutically
active substance with the unacceptable taste is presented in a less
soluble form prior to formation of said system.
3. The process according to claim 1 wherein the carrier material is
gelatin.
4. The process according to claim 1 wherein the discrete units are
selected from the group consisting of liquid, frozen and gelled
units.
5. The process according to claim 4 wherein the discrete units are
formed in a mold comprising a plurality of pockets.
6. The process according to claim 4 wherein the discrete units are
liquid units which are frozen prior to removal of the solvent.
7. The process according to claim 4 wherein the discrete units are
frozen units and the solvent is removed by freeze drying.
8. The process according to claim 4 wherein said units are frozen
liquid units and said solvent is removed by vacuum drying under
conditions whereby the solvent is evaporated from said frozen units
through the liquid phase to a gas.
9. The process according to claim 4 wherein the discrete units are
gelled units from which the solvent is removed by during under
conditions selected from the group consisting of decreased pressure
and forced air drying.
10. The process according to claim 5 wherein the mold comprises at
least one depression in a sheet of a filmic material.
11. The process according to claim 10 wherein a sheet of a covering
material is adhered to a filmic material in the area around at
least one said depression after the removal of solvent from said
system.
12. The process according to claim 1 wherein the pharmaceutically
active substance is loperamide hydrochloride which is converted
into the form of the loperamide free base during the preparation of
the system.
13. The process according to claim 1 wherein the less soluble
pharmaceutically active substance is free domperidone base.
14. A solid, oral, rapidly disintegrating dosage form of a
pharmaceutically active substance prepared by a process according
to claim 1.
15. A solid, oral, rapidly disintegrating dosage form according to
claim 14 wherein the pharmaceutically active agent is loperamide
which is present in the composition in the form of the loperamide
free base.
16. A solid, oral, rapidly disintegrating dosage form comprising
loperamide free base as the pharmaceutically active substance in a
network of a carrier material selected from the group consisting of
water-soluble and water-dispersible carrier materials.
Description
RELATED APPLICATIONS
[0001] The present application is a continuation of U.S. patent
application Ser. No. 09/551,361 filed Apr. 18, 2000, which is a
continuation-in-part of application Ser. No. 09/026,551 filed Feb.
20, 1998 which is a continuation of application Ser. No.
08/330,936, filed Oct. 28, 1994, now U.S. Pat. No. 5,738,875.
FIELD OF THE INVENTION
[0002] The present invention relates to a process for preparing
solid pharmaceutical dosage forms and, in particular, to a process
for preparing a solid, oral, rapidly disintegrating dosage form of
a pharmaceutically active substance which has an unpleasant
taste.
BACKGROUND OF THE INVENTION
[0003] Many pharmaceutically active substances are presented for
oral administration in the form of conventional oral dosage forms,
including tablets, pills or capsules. The tablet, pill or capsule
generally has to be swallowed with water so that the
pharmaceutically active substance can be absorbed via the
gastrointestinal tract. For some patients, swallowing the tablet,
pill or capsule is difficult or impossible and this is particularly
the case for pediatric patients and geriatric patients. A similar
difficulty is often encountered when trying to administer tablets
to non-human animals which may be uncooperative in taking tablets,
pills or capsules.
[0004] Oral solid pharmaceutical dosage forms which rapidly
disintegrate in the mouth and methods for their preparation have
been proposed in GB-A-1548022 and GB-A-2111423. The solid dosage
forms, as disclosed in these references, comprise an open matrix
network carrying the pharmaceutically active substance, the open
matrix comprising a water-soluble or water-dispersible carrier
material which is inert towards the pharmaceutically active
substance. The solid dosage forms are prepared by the sublimation
or removal of solvent from a solution or suspension comprising the
pharmaceutically active substance and the carrier material.
Sublimation or removal of solvent is preferably carried out by
freeze drying.
[0005] U.S. Pat. No. 5,382,437 to Ecanow discloses a readily
dissolved carrier composition suitable for use in administration of
drugs and foodstuffs. The composition comprises a skeletal
structure produced by contacting a gel and a rigidifying material
for the gel with liquified ammonia at low temperature until the
mass solidifies. As the mass is slowly warmed to ambient
temperature under vacuum, the solid ammonia sublimes from the solid
state to the gas state to provide a porous drug or foodstuff
delivery system.
[0006] Other methods for the preparation of oral solid
pharmaceutical dosage forms which rapidly disintegrate in the mouth
are disclosed in U.S. Pat. Nos. 4,855,326; 5,039,018; 5,120,549;
5,330,763; PCT/JP93/01631; PCT/US93/125661 and WO 98/57648, which
are incorporated herein by reference.
[0007] The solid dosage forms which are produced by these various
methods rapidly disintegrate on being placed in th mouth of the
patient, thereby delivering the desired dose of the
pharmaceutically active substance.
[0008] Although the solid dosage forms as described above overcome
the problems of swallowing tablets, pills or capsules, the patient
will taste the pharmaceutically active substrate as the dosage form
disintegrates. For some pharmaceutically active substances, the
taste, if slightly unpleasant, can be rendered acceptable by the
use of sweetening agents, flavoring agents and the like, which mask
the taste. Yet, in some pharmaceutically active substances, the
unpalatable taste will still exist, despite the use of sweetening
agents and flavoring agents. In those instances in which
over-flavoring techniques alone will not suffice, the
insolubilization techniques of the present invention can result in
palatable formulations.
SUMMARY OF THE INVENTION
[0009] Through the efforts of the present inventors, a new method
for the preparation of a solid, oral, rapidly disintegrating dosage
form of a pharmaceutically active substance which has an
unacceptable taste has been developed, which does not wholly depend
upon trying to mask the unacceptable taste by the use of sweetening
agents, flavoring agents and the like. In general, the present
invention uses the less soluble form to the drug to reduce or
eliminate the use of sweetening agents, flavor and the like.
[0010] In a first aspect, the present invention provides a process
for the preparation of a solid, oral, rapidly disintegrating dosage
form of a pharmaceutically active substance which has an
unacceptable taste. The process comprises forming a solution or a
suspension in a solvent of a form of the pharmaceutically active
substance which is less soluble in water than th form with the
unacceptable taste, together with a water-soluble or
water-dispersible carrier material, forming discrete units of the
solution or suspension. The solvent is then removed from the
discrete units under conditions whereby a network of the carrier
material carrying a unit dosage of the less soluble form of the
pharmaceutically active substance is formed.
[0011] In another aspect, the invention provides a rapidly
disintegrating dosage form of a pharmaceutically active substance
when prepared by the process of the invention.
[0012] The present invention also includes within its scope, a
solid, oral, rapidly disintegrating dosage form of a
pharmaceutically active substance which has been rendered more
palatable by the process as described above.
[0013] The present invention is also directed to a solid, oral,
rapidly disintegrating dosage form comprising loperamide free base
as the pharmaceutically active substance in a network of a carrier
material selected from the group consisting of water-soluble and
water-dispersible carrier materials.
[0014] Further, the invention discloses a solid, oral, rapidly
disintegrating dosage form comprising domperidone free base as the
pharmaceutically active substance in a network of a carrier
material selected from the group consisting of water-soluble and
water-dispersible carrier materials.
DETAILED DESCRIPTION OF THE INVENTION
[0015] As used herein and in the claims, the term "rapidly
disintegrating" means that the solid dosage form will disintegrate
in water at 37.degree. C. in 60 seconds or less, preferably 5 to 10
seconds or less, when tested by the following procedure which is
analogous to the Disintegration Test for Tablets, B. P. 1973 and
which is further described in British Patent No. 1548022.
[0016] Disintegration Test--Apparatus
[0017] A glass or suitable tube 80 to 100 mm long, with an internal
diameter of about 38 mm and an external diameter of 30 to 31 mm and
fitted at the lower end so as to form a basket, with a disc or
rustproof wire gauze complying with the requirements for a No. 1.70
sieve (B. P. 1983, page A136).
[0018] A glass cylinder with a flat base and an internal diameter
of about 45 mm containing water and not less than 15 cm deep at a
temperature between 36.degree. C. and 38.degree. C.
[0019] The basket is suspended centrally in the cylinder in such a
way that it can be raised and lowered repeatedly in a uniform
manner so that at the highest position, the gauze just breaks the
surface of the water and at the lowest position, the upper rim of
the basket just remains clear of the water.
[0020] Method
[0021] Place one shaped article (the rapidly disintegrating dosage
form) in the basket and raise and lower it in such a manner that
the complete up and down movement is repeated at a rate equivalent
to thirty times a minute. The shaped articles are considered
disintegrated when no particle remains above the gauze which would
not readily pass through it.
[0022] On oral administration of the solid dosage form of the
invention to a patient, the pharmaceutical dosage form rapidly
disintegrates in the mouth. The rapidly disintegrating dosage form
of the present invention enables poorly tasting pharmaceutically
active substances to be presented in a palatable form without
changing the bioavailability of the pharmaceutically activ
substance relative to an existing solid dosage form (i.e., pills
and tablets) containing the more soluble compound. The
pharmaceutically active substance is presented as a less soluble
form rendering less of the drug to be tasted as the solid dosage
form dissolves disintegrates in the saliva.
[0023] The pharmaceutically active substance with the unacceptable
taste may be presented in less soluble form prior to formation of
the solution or suspension. Alternatively, the pharmaceutically
active form may be converted into the less soluble form during the
process of the invention, for example during the preparation of the
solution or suspension.
[0024] The pharmaceutically active substance with the unacceptable
taste may be rendered less soluble by conversion of a salt to a
free acid or a free base, or conversion of a free base to a salt,
or changing the salt form to a less soluble salt form, or by using
the common ion effect or salting out, or changing the polymorphic
form thereof, or by adjusting the pH, or by any other suitable
means. Each of these conversion approaches may be carried out using
methods well known to persons of ordinary skill in this art. In the
publication "Pharmaceutics--The Science of Dosage Form Design"; Ed.
M. E. Aulton, Churchill Livingstone provides a general discussion
of methods for conversion of drugs to forms of different
solubility. The teachings of this reference are incorporated herein
by reference.
[0025] The conversion of a salt to a free acid or free base may be
carried out, for example, by the addition of an amount of acidic or
alkaline agent to the salt and mixing of the resultant suspension
until the solid salt has been neutralized to the free base form.
The salt may be dispersed in an appropriate amount of water along
with the acidic or alkaline agent and any other excipients required
to produce the dosage form. This mixture is then mixed continuously
until the solid salt has been converted to the respective free base
or free acid. The amount of acidic or alkaline agent needed is
determined experimentally by preparing formulations with varying
amounts of the agent and performing taste assessments on the
finished product.
[0026] As a typical example of a salt to a free base, the
hydrochloride salt, e.g. Loperamide hydrochloride, may be converted
to the free base using a bicarbonate buffer, such as for example
sodium hydrogen carbonate buffer.
[0027] Conversion of a salt form to a less soluble salt form may be
achieved by dispersing the salt in an aqueous medium and then
adding the required amount of an appropriate excipient salt. An
appropriate excipient salt is one which contains a counter-ion of
opposite charge to the dissolved drug and which has a stronger
affinity for the drug than the counter-ion in the original drug
salt. This mixture is agitated until the conversion is complete.
The amount of acidic or alkaline agent needed is determined
experimentally by preparing formulations with varying amounts of
the agent and performing taste assessments on the finished
product
[0028] Pages 227-229 of Pharmaceutics, supra, illustrates methods
for calculation of the pH of a drug, the susceptibility of that
drug to salt formation and the type of salt that can be formed.
Examples of pharmaceutically acceptable salts are hydrochloride,
sulfate, besylate, maleate, tartrate, benzoate and citrate. By way
of example of the effect of a particular salt form on solubility,
for the drug Chlordiazepoxide, the following illustrates the
differences in solubility of the different salts of the drug.
Chlordiazepoxide sulfate or besylate are freely soluble whereas
Chlordiazepoxide base has a solubility of about 2.0 mg ml.sup.-1.
Chlordiazepoxide maleate has a higher solubility of about 57.1 mg
ml.sup.-1 whereas Chlordiazepoxide tartrate has a solubility of
17.9 mg ml.sup.-1, Chlordiazepoxide benzoate has a solubility of
6.0 mg ml.sup.-1 and Chlordiazepoxide acetate has a solubility of
4.1 mg ml.sup.-1.
[0029] The common ion effect or salting out may be used to reduce
the solubility. This is achieved by the addition of a soluble
electrolyte if this contains a common ion to the drug to be
dissolved. In effect, the drug and the additional electrolyte are
competing for the solvent, which in turn reduces the solubility of
the drug. An example of the common ion effect (or salting out) is
the addition of sodium bromid to a near-saturated solution of
dextromethorphan hydrobromide to effect precipitation of at least a
portion of the drug. The effect may be explained with reference to
the solubility product, the constant equilibrium value of the
product of the concentrations of the two ionic species arising from
the drug. An added excess of one ion in the form of a soluble salt
will cause the solubility product to be exceeded, and this will b
corrected by removal of a proportion of both drug ions by
precipitation of solid drug.
[0030] The formation of a hydrate is typically achieved by stirring
a suspension of the drug in water to effect conversion of the drug
to the hydrate. Piroxicam monohydrat is produced progressively when
a suspension of anhydrous piroxicam is stirred in water.
[0031] The polymorphic form may be changed in order to present the
pharmaceutically active substance with the unacceptable taste in
less soluble form prior to formation of the solution or suspension.
Polymorphs are solid materials with at least two different
molecular arrangements, each of which has a distinct crystal
structure. The particular crystal state of a solid depends, at
least in part, on the solvent(s) used for recrystallization.
Different polymorphic forms have different stabilities, different
oral bioavailabilities and different solubilities. A discussion of
the phenomenon of polymorphism appears in WO 98/57648. The
solubility of a crystalline form generally decreases with the
increase in melting point of the crystalline form. Inter-conversion
of polymorphs can occur spontaneously. The selection of a less
soluble polymorph can also be carried out by solvent manipulation,
or by thermal techniques, notably sublimation and recrystallization
from the melt. These techniques are well known to persons of
ordinary skill in this art.
[0032] The solubility of weak acids and weak bases may be adjusted
by pH control. Increasing the pH of a solution can decrease
solubility of a weak base, whereas the solubility of a weak acid
can be decreased by a pH decrease. The relative levels of weak acid
or weak base added to the drug can be calculated with the knowledge
of the Henderson-Hasselbalch equation, and by calculation of the
pKa of the drug concerned in the solvent in question.
[0033] For example, where Piroxicam is the drug of interest, the pH
may be adjusted in a manner which changes the ratio of the
unionized to ionized species, which in turn provides for an
approximately tenfold decrease in solubility, and a significant
reduction in the bitter taste of the drug. Piroxicam (Feldene) has
a "U"-shaped pH solubility curve with a minimum around pH 3.5.
Typically, when Piroxicam is used in the system of the present
invention, it exhibits a pH of about 6.5. This may be adjusted to
approximately 4.0 by addition of an add such as citric acid to
produce the approximately tenfold decrease in solubility. This
results in a significantly reduced bitter taste by reducing the
amount of dissolution in the mouth. A further advantag arising out
of th reduced solubility of Piroxicam is reduced formation of the
hydrate which has a bright yellow color.
[0034] Other ways of rendering the pharmaceutically active form
less soluble are reducing the solubility of highly hydrophilic
drugs in the presence of an organic co-solvent. Bulking with less
hydrophilic water-soluble solutes may have a similar effect.
[0035] The discrete units of the suspension or solution may be in
the form of liquid units, for example contained within the pockets
of a suitable mold. The liquid units may alternatively be in the
form of gelled units where the carrier material readily forms a
gel. These liquid units are then preferably frozen and the solvent
removed via freeze drying. The removal of solvent from the discrete
units comprising the pharmaceutically active substance in its less
soluble form and a water-soluble or water-dispersible carrier
material may also be carried out by other techniques well known to
those skilled in the art. When the discrete units are in liquid
form, they will generally be frozen or gelled prior to drying.
[0036] The liquid solution or suspension which may be contained
within the pockets of a suitable mold is frozen, for example by
passing a gaseous cooling medium, such as liquid nitrogen over the
mold, or by inserting the mold into a nitrogen spray freezing
chamber, or cooling by passing the mold over a cold surface. Once
the dosage forms have been frozen, the mold may be stored in a cold
store, prior to drying. Frozen discrete units may be dried by
freeze drying according to techniques which are well known in the
art. The solvent is sublimed in a freeze drying process under a
reduced pressure which transforms the solid solvent directly into a
vapor. The freeze drying process will generally be carried out in a
freeze drying chamber typically operating under a vacuum of 0.1 to
1.0 mbar for a period of time of from 180 to 500 minutes.
[0037] Alternatively, frozen discrete units may be dried by a
process as described in U.S. Pat. Nos. 5,120,549 and 5,330,763. In
this method, the pharmaceutically active substance and carrier
material dispersed in a first solvent is solidified and th
solidified matrix is subsequently contacted with a second solvent
that is substantially miscible with the first solvent at a
temperature lower than the solidification point of the first
solvent, the matrix component being substantially insoluble in the
second solvent, the first solvent thereby being removed from the
matrix.
[0038] Another alternative process for drying frozen discrete units
is described in WO94/14422. In this process the solvent is removed
under conditions whereby the solvent is evaporated from the solid
through the liquid phase to a gas, rather than subliming from a
solid to a gas as in lyophilization. This is achieved by vacuum
drying at a temperature below the equilibrium freezing point of the
composition at which point the solvent (such as water) changes
phase.
[0039] When the discrete units are gelled units, any drying method
can be used which does not affect the properties of the
preparations. For example, drying may be carried out at decreased
pressure, or by forced-air drying. Drying at decreased pressure is
preferably carried out at a temperature of from 25.degree. to
35.degree. C. under a vacuum of -750 mm Hg or less, for 2 to 5
hours, while drying using forced-air drying is preferably carried
out at a temperature of from 30 to 15.degree. C. for 1 to 6
days.
[0040] The solvent used in forming the solution or suspension of
the pharmaceutically active substance is preferably water but it
may be admixed with a co-solvent, such as alcohol, if it is desired
to improve the solubility of the active substance.
[0041] The carrier material which is used to form the network
containing the pharmaceutically active substance may be any
water-soluble or water-dispersible material that is
pharmaceutically acceptable, inert to the pharmaceutically active
substance and which is capable of forming a rapidly disintegrating
network. The preferred carrier material for use in the present
invention is gelatin, preferably pharmaceutical grade gelatin.
[0042] Other materials may also be used, for example hydrolyzed
dextrose, dextran, dextrin, maltodextrin alginates,
hydroxyethylcellulose, sodium carboxymethylcellulose,
microcrystalline cellulose, corn-syrup solids, pectin, carrageenan,
agar, chitosan, locust bean gum, xanthan gum, guar gum, acacia gum,
tragacanth, konjac flour, rice flour, wheat gluten, sodium starch
glycolate, soy fiber protein, potato protein, papain, horse radish
peroxidase, glycine or mannitol.
[0043] The suspension or solution prepared according to the process
of the present invention is preferably formed into discrete units
by introduction into a mold which preferably comprises a plurality
of depressions, each depression being of the desired shape and size
for the oral dosage form product. The mold preferably comprises a
plurality of depressions formed in a sheet of a filmic material
which may be similar to the material employed conventionally in the
blister packaging of pharmaceuticals. A particularly preferred
filmic material for use as a mold in the present invention is
described in WO94/12142. The desired quantities of the suspension
or solution may be filled into the mold using an automatic filling
means which delivers a predetermined dose into each of the
depressions in the mold.
[0044] A covering material may be adhered to the filmic material in
the area surrounding the depressions after the removal of solvent
from the solution or suspension filling the depressions. The
covering sheet is preferably an aluminum foil or aluminum foil
laminate which may be adhered to the filmic material around the
depressions by, for example a heat sensitive material. The cover
sheet may be adhered to the filmic material in a manner such that
it can be peeled away by the user to uncover the oral dosage form
in the depression in the mold or, alternatively, it may be adapted
for the oral dosage forms to be pushed through.
[0045] Alternative methods of forming discrete frozen or gelled
units of the solution or suspension include solidifying the
mixtures in dropwise fashion. For example, the solution or
suspension may be passed through one or more holes to form drops,
spheres or a spray of small particles which can be solidified by
passage through a cold gas or liquid, for example liquid nitrogen.
Alternatively, the drops, spheres or spray may be solidified by
contact with a chilled liquid which is miscible with the solution
or suspension and which has a density such that the drops either
fall through the miscible liquid as they solidify, or float on the
surface of the miscible liquid.
[0046] The suspension or solution prepared in accordance with the
process of the present invention may also contain other additional
ingredients such as coloring agents, flavoring agents, sweetening
agents or preservatives, or fillers such as mannitol or sorbitol
which improve the physical properties of the oral dosage form.
[0047] The product produced by U.S. Pat. No. 5,382,437 to Ecanow is
generally dimensionally larger than the product of the present
invention. Based on the data appearing in Example 1 of this
reference, a product would be produced which has a diameter
approximately four to five times larger than the thickness. Thus,
for a thickness of about 4 mm, the Ecanow product would have a
diameter of about 3 cm. In the present invention, the product is
dimensionally small r and generally has a diameter of about 1 to
1.5 times the thickness of the product. For a thickness of 4 mm,
the diameter may be of the order of about 7 mm.
[0048] The process of the present invention may be used to prepare
rapidly disintegrating dosage forms of various pharmaceutically
active substances which have an unacceptable taste. For example,
loperamide is incorporated into conventional tablets in the form of
its hydrochloride which has an unacceptable taste for formulation
into a rapidly disintegrating dosage form. However, the use of
loperamide in the form of the-free base enables a palatable dosage
form to be produced. Similarly, domperidone is incorporated into
conventional tablets in the form of its maleate which has an
unacceptable taste for formulation into a rapidly disintegrating
dosage form. However, the use of domperidone in the form of the
free base enables a palatable dosage form to be produced.
[0049] An advantage of the use of the less soluble forms of the
pharmaceutically active substances in the process of the present
invention is that the less soluble forms are generally easier to
freeze dry, vacuum dry or dry conventionally.
[0050] The process of the present invention for making more
palatable rapidly disintegrating dosage forms obviates the need to
use costly drug coating techniques or complexation techniques to
mask the taste of the pharmaceutically active substance. The
present invention will be further described with reference to the
following Examples, which are intended to be illustrative and not
limitative.
EXAMPLE 1
[0051] A solid, oral, rapidly disintegrating dosage form of
loperamide was prepared from loperamide hydrochloride using the
following ingredients:
1 QUANTITIES FOR INGREDIENTS 400 UNITS Loperamide hydrochloride
0.800 g Gelatin 2.345 g Mannitol 1.759 g Aspartame 0.300 g Mint
flavor 0.120 g Sodium hydrogen carbonate 0.150 g Purified water
54.526 g
[0052] The gelatin was added to water in a mixing bowl and heated
with mixing to approximately 40.degree. C. The mixture was mixed
and homogenized under vacuum until dissolution of the gelatin was
complete.
[0053] The gelatin solution was added to a mixture of mannitol,
sodium hydrogen carbonate and loperamide hydrochloride and the
mixture mixed and homogenized until the soluble components had
dissolved and the dispersion of the drug particles was complete.
The mixture was cooled under vacuum and aspartame and mint flavor
added thereto.
[0054] The suspension was dosed into blister pockets, frozen and
freeze dried to produce the final dosage form. During the
processing the loperamide hydrochloride was converted into the less
soluble loperamide free base form by the sodium hydrogen carbonate
buffer.
[0055] The product had an acceptable taste.
EXAMPLE 2
[0056] Domperidone maleate is a poor tasting pharmaceutical
compound and when initially formulated as a freeze dried rapidly
disintegrating oral dosage form, produced an unacceptable
product.
[0057] Domperidone was formulated in the form of the free base
(which is less soluble in water or saliva than domperidone maleate)
into a solid, oral, rapidly disintegrating dosage form using the
following ingredients.
2 WEIGHT INGREDIENTS PER UNIT Domperidone (free base) 10 mg
Aspartame 0.75 mg Peppermint flavor 0.15 mg Gelatin 5.70 mg
Mannitol 5.20 mg Purified water 128.20 mg
[0058] A solution containing the gelatin and mannitol was prepared
and to this was added the aspartame and peppermint flavor. Aliquots
of the resulting solution were added to the domperidone powder and
a paste formed on stirring. The remainder of the solution was added
and homogeneous suspension obtained. The suspension was dispensed
in 150 mg aliquots into the pockets of a blister pack, frozen and
freeze dried to produce the final dosage form.
[0059] The product had an acceptable taste.
EXAMPLE 3
[0060] The following is an example of conversion of a salt to a
free base. A mixture was formed with the following ingredients:
3 WEIGHT INGREDIENTS PER UNIT Loperamide Hydrochloride 12 g Sodium
hydrogen carbonate 2.5 g Gelatin 35 g Mannitol 26 g Water 825.5
g
[0061] The mixture was agitated mixed using a high shear mixer
until the loperamide salt was converted to the free base. This was
determined by monitoring the change in crystal morphology using a
microscope. The mixture is then dosed into blister pockets, frozen
and freeze dried to produce the final dosage form.
EXAMPLE 4
[0062] The following is an example conversion of a salt to a free
acid. A mixture was formed as follows:
4 WEIGHT INGREDIENTS PER UNIT Diclofenac Potassium 50 g Citric Acid
50 g Gelatin 20 g Mannitol 15 g Water 365 g
[0063] The mixture was agitated using a high shear mixer until the
conversion was completed. This was determined by monitoring the
change in crystal morphology using a microscope. The mixture is
then dosed into blister pockets, frozen, and freeze dried to
produce the final dosage form.
EXAMPLE 5
[0064] The following is an example of formation of a hydrate.
Hydrates of some drugs have a reduced solubility compared to the
anhydrous forms. The formation of a hydrate may be achieved by
suspending the drug in an aqueous medium and agitating until the
respective hydrate is formed. This process can be accelerated by
using heat and a high shear mixing. A suspension was formed using
the following ingredients:
5 WEIGHT INGREDIENTS PER UNIT Thyroxine sodium 1 g Water 500 g
[0065] The suspension was agitated until the thyroxine salt was
converted to the hydrate form. This was determined by monitoring
the change in crystal morphology using a microscope.
[0066] Industrial Applicability
[0067] While the invention has been described in connection with
what is presently considered to be the most practical and preferred
embodiment, it is to be understood that the invention is not to be
limited to the disclosed embodiment, but on the contrary, is
intended to cover various modifications and equivalent arrangements
included within the spirit and scope of the appended claims.
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