Note: Descriptions are shown in the official language in which they were submitted.
CA 02506712 2001-06-22
Rapidly disintegrating dosage form for releasing active
ingredients in the oral cavity or in body cavities
The invention relates to preferably sheet-like dosage forms
which rapidly disintegrate in an aqueous environment, in
particular oral dosage forms, which make possible rapid
release of active ingredients in the oral cavity or in
other body orifices or body cavities and which have a
matrix based on water-soluble polymers as base substances.
The invention relates in particular to dosage forms of the
type mentioned which are in the form of wafers. The
invention also includes processes for the production of
such dosage forms.
Pharmaceutical dosage forms, e.g. buccal or sublingual
tablets, which release active ingredients in the oral
cavity, which are then absorbed through the oral mucosa are
advantageous in many respects. They facilitate oral
administration of medicaments to certain patients who have
difficulty in taking other oral drug forms - e.g. because
of problems with swallowing. Since absorption via the oral
mucosa avoids passage through the gastrointestinal tract, a
rapid onset of action and extensive utilization of active
ingredient are ensured. Said advantages also apply to
vaginal, rectal and intranasal administration forms.
Suitable oral drug forms which have the aforementioned
properties are, beside sublingual or buccal tablets, also
sheet-like, wafer-like dosage forms (called wafers).
Because their thickness is low and they are capable of
rapid disintegration or dissolution they are distinguished
in particular by rapid release of medicaments and other
active ingredients in the oral cavity. Such wafer-like drug
forms are usually composed of film-forming, water-soluble
polymers such as, for example, certain cellulose
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derivatives. On contact with water or saliva, the polymers
dissolve and the drug form disintegrates, releasing the
active ingredients present therein. The onset and the time
course of release of active ingredient depend to a great
extent on the thickness of the drug form (of the wafer);
the thinner it is, the more rapidly disintegration
progresses in an aqueous environment, because the solvent
can penetrate faster into the inner regions of the drug
form. On the other hand, such drug forms (wafers) must have
a certain thickness in order to be able to comply with
their intended function, namely to deliver active
ingredients. Consequently, the thickness of such dosage
forms is essentially determined by the nature and amount of
the active ingredient which they contain and are intended
to release. As the thickness increases, the disintegration
or dissolution of the wafer becomes correspondingly slower.
Thicker wafers in particular, but also those with a
relatively low thickness, are prone, because of their
sheet-like, smooth shape and the retarded disintegration,
to stick and become firmly adherent to the roof of the
mouth or other surfaces of the oral mucosa. This is caused
by the polymer layers dissolving on the surface, which form
a tacky and viscid film.
The property of these drug forms of becoming firmly
adherent to the.roof of the mouth and other surfaces of the
oral mucosa may cause an unpleasant sensation for the
relevant person or for the patient, i.e. the mouthfeel
caused by these wafers is unpleasant or upsetting and
therefore in need of improvement.
EP 0 450 141 B2 discloses a carrier material for the
administration of drugs which rapidly dissolve on contact
with saliva after oral intake. This carrier material has a
porous dehydrated skeletal structure and is based, in
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particular, on proteins and polysaccharides. The cavities
produced by dehydration are used for incorporation of
liquid active substances. The gelatin/polysaccharide
carriers described can also be used in the form of wafers.
No measures are provided for reducing the tendency to
stick; this risk does exist, however, because the
dehydrated carrier materials are rehydrated on contact with
saliva at the latest and thus acquire a tacky surface.
It was therefore the object of the present invention to
provide a dosage forma, in particular an oral dosage form of
the aforementioned type, which displays the known
advantages of sheet-like, rapidly disintegrating dosage
forms and additionally has a reduced tendency to stick or
adhere.to the oral mucosa and is therefore distinguished by
an improved mouthfeel.
The object is achieved according to the invention by
providing a dosage form having the features specified in
the preamble to claim 1 with spaces or cavities which are
present in the polymeric matrix of the dosage fona and
whose contents differ in terms of the state of aggregation
from the matrix. This means in particular that the spaces
or cavities comprise gaseous,or liquid contents, while the
polymer matrix itself has a solid or semisolid state of
aggregation. The dosage forms of the invention thus have
spatial regions with different phases; said spaces or
cavities represent a second phase which may be present in
the interior of the polymer matrix (first phase), but it
may also extend as far as the outer edge.
On the one hand, the spaces or cavities of the invention
facilitate access of water or saliva or other body fluids
into the interior of the dosage form (e. g. wafer) and thus
speed up the dissolution of the dosage form and the release
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of active ingredient, which represents an advantage in
particular with thicker dosage forms (wafers). On the other
hand, the thickness of the walls of said spaces or cavities
is low because they represent, for example, solidified
bubbles, so that a rapid dissolution or disintegration of
these cavities takes place. This altars the internal
structure and, as a consequence, also the surface of the
dosage form, so that the surface becomes irregular. For
example, the surface thus acguires a corrugated structure
or irregularities. This and the stiffness of the product
prevent the wafer sticking to the oral mucosa.
Because the tendency to stick is reduced, the dosage forms
of the invention are distinguished by an improved
mouthfeel, which eventually leads to improved acceptance by
the users or patients.
The residence time of the dosage forms of the invention at
the site of administration (e.g. oral cavity) or the
disintegration time is preferably in the range from 1 s to
min, more preferably in the range from 5 s to 1 min, and
most preferably in the range from 10 s to 30 s.
The invention is not, however, confined to oral dosage
forms which release active ingredients in the region of the
oral cavity. On the contrary, it also extends to dosage
forms which are introduced into other body cavities or body
orifices and release their active ingredients there, for
example rectal, vaginal or intranasal dosage forms. The
released active ingredient is either absorbed at the site
of administration, e.g. through the oral mucosa, or it is
transported further and absorbed at another site (e.g. in
the gastrointestinal tract after the active ingredient
released in the oral cavity has bean swallowed).
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Said spaces or cavities of the dosage form may each be
present isolated from one another in the polymeric matrix
or preferably in the form of solidified bubbles. Another
embodiment provides for said spaces or cavities to be
connected to one another, preferably forming a connected
channel system penetrating through the matrix.
Suitable dosage forms having the spaces or cavities of the
invention are, in particular, polymeric materials which
represent solidified foams.
Said spaces or cavities are preferably filled with gas or a
gas mixture, in particular air; however, it may also be
advantageous for them to contain other gases or gas
mixtures. A further embodiment provides for the spaces or
cavities to be filled with a liquid or a liquid mixture
(for example oils), these liguids not being miscible with
the matrix material and not dissolving the polymeric
framework. Said liquid or the liquid mixture may
additionally comprise one or more active pharmaceutical
ingredients.
The total volume of said spaces or cavities, as a
proportion of the total volume of the dosage form, is
preferably from 5 to 98%, with preference for 50-80%. In
this way the intended adhesion-diminishing effect is
achieved without impairing too greatly the capacity of the
dosage form to take up active ingredient.
Another important parameter influencing the properties of
the dosage forms of the invention is the diameter of the
cavities or bubbles. The bubbles or cavities are preferably
produced using a foam-beating machine. It is thus possible
to adjust the diameter of the bubbles in a wide range
almost as desired. Thus, the diameter of the bubbles or
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cavities can be in the range from 0.01 to 50 dim; diameters
between 0.1 and 10 dim are particularly preferred.
The cavities of the dosage forms of the invention are
preferably free of active ingredient; however, it may be
advantageous for these cavities to contain excipients or
additives, preferably surfactants or gas-forming
substances.
In order to diminish further the tendency of the dosage
forms to stick it is possible additionally to make use of
the measure of giving the surfaces of the dosage form an
uneven or irregular shape, preferably corrugated or like a
relief or with a structured surface. Such an irregular
surface structure can be caused, for example, by the
bubble-like cavities introduced into the polymer matrix
and/or by a subsequent special drying treatment.
The matrix of the dosage forms of the invention comprises
as base substances a water-soluble polymer or mixtures of
such polymers. Preferably used for this purpose are
synthetic or partially synthetic polymers or biopolymers of
natural origin, which are film-forming and water-soluble
and/or which are suitable for foam formation.
Particularly suitable polymers are those preferably
selected from the group comprising cellulose derivatives,
polyvinyl alcohol, polyacrylates and polyvinylpyrrolidone.
Particularly preferred cellulose derivatives are
hydroxypropylmethylcellulose, carboxymethylcellulose,
hydroxypropylcellulose, hydroxymethylcellulose,
methylcellulose, and other substituted cellulose
derivatives. Likewise preferred are water-soluble
polysaccharides of vegetable, microbial or synthetic
origin, in particular those polysaccharides which are not
cellulose derivatives, such as, for example, pullulan,
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xanthan, alginates, dextrans, agar-agar, pectins and
carrageenan; the last-mentioned is particularly preferred.
Also suitable are proteins, preferably gelatin or other
gel-forming proteins, and protein hydrolyzates. Suitable
protein hydrolyzates include, inter alia, caseinate, whey
and vegetable proteins, gelatin and (egg) albumin, and
mixtures thereof.
Preferred proteins are caseinates derived from spray-dried
dairy products.
The dosage forms of the invention are preferably thin, e.g.
in the form of a wafer. The thickness of the dosage form is
preferably between 0.1 and 5 mm, particularly preferably
between 0.5 and 1 mm. The lower limit for the thickness of
the dosage forms is about 50 ~.tm.
Suitable active ingredients are therapeutically active
compounds - without restriction. These may be derived from
the following groups: agents for treating infections;
virostatics; analgesics such as fentanyl, sufentanil,
buprenorphine; anesthetics, anorectics; active ingredients
for treating arthritis and asthma, such as terbutaline;
anticonvulsants; antidepressants; antidiabetics;
antihistamines; antidiarrheals; agents for migraine,
pruritus, nausea and retching; travel and sea sickness,
such as scopolamine and ondansetron; anti-parkinson agents;
antipsychotics; antipyretics, spasmolytics,
anticholinergics, anti-ulcer agents such as ranitidine,
sympathomimetics; calcium channel blockers such as
nifedipine; beta blockers; beta agonists such dobutamine;
antiarrhythmics; antihypertensives such as atenolol; ACE
inhibitors such as enalapril; benzodiazepine agonists such
as flumazenil; coronary, peripheral and cerebral
vasodilators; stimulants for the central nervous system;
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hormones; hypnotics; immunosuppressants; muscle-relaxing
agents; parasympatholytics; parasympathomimetics;
prostaglandins; proteins, peptides; psychostimulants;
sedatives; tranquilizers.
Suitable active ingredients for administration in the mouth
or onto the oral mucosa are in principle all those able to
undergo buccal and/or gastrointestinal absorption. Among
these, nicotine is particularly preferred.
The active ingredient content per dose unit is up to 50 mg,
preferably up to 30 mg, particularly preferably up to
20 mg.
Further suitable active ingredients are:
polishers, abrasives such as titanium dioxide, silicon
dioxide etc.; sodium fluoride, dicalcium phosphate;
essential oils such as aniseed oil, fennel oil, eucalyptus
oil, peppermint oil, spearmint oil, orange oil, sage oil,
thyme oil, lemon oil etc.; aromatizers such as camphor,
cineol, eucalyptol, menthol, pinene, cinnamaldehyde,
cinnamic acid, etc.; honey, citric acid, vitamins,
antioxidants, sorbitol.
The dosage forms of the invention are thus also suitable
for cosmetic applications and for uses in the areas of
dental care, tooth cleaning, oral hygiene or dental
hygiene.
Further aromatizers which can be added are vanilla flavor,
orange flavor, orange zest flavor, strawberry flavor,
raspberry flavor or chocolate flavor, each singly or in
combination. It is additionally possible to add one or more
sweeteners such as sucralose, aspartame, cyclamate,
saccharin and acesulfame, and salts thereof.
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Suitable excipients are, inter alia, substances from the
following group:
carboxymethylcelluose, gum arabic, methylcellulose,
pectins, modified and unmodified starches, gelatin, animal
and/or vegetable proteins, egg albumin, alginates, Brij (an
emulsifier), isopropanol, benzyl alcohol, ethyl acetate,
ethyl citrate, octyl gallate, 1,2-propylene glycol,
magnesium stearate, stearic acid, microcrystalline
cellulose, Aerosil, lecithin, Tween, propyl gallate,
amylogam.
It is additionally possible to dissolve a sugar (or a
mixture of sugars) or another carbohydrate material in the
foam. The sugar or the carbohydrate increases the mass
which the foam has after drying. In addition, the drying
and the crystallization of the sugar or of another
carbohydrate confers on the dried foam an additional
strength and stability. The sugar or other carbohydrates
may result in the dried foam having a sweet taste or may
improve the organoleptic properties of the foam in other
ways. Examples of sugars which can be used for this purpose
are, inter alia, maltose, lactose, sucrose, dextrose
(glucose) and trehalose, and sugar alcohols such as, for
example, mannitol, sorbitol, xylitol, maltitol, and the
like. Examples of other suitable carbohydrates are
maltodextrin, starch sugar syrup (from corn), soluble
starches and the like.
During production of the dosage forms of the invention it
is additionally possible to admix one or more acids in
order to confer on the foam a pleasant acidic taste.
Examples of such acids include, inter alia, citric acid,
lactic acid, acetic acid, benzoic acid, propionic acid,
oxalic acid, malonic acid, succinic acid, malic acid and
tartaric acid. The addition of acids) may additionally be
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necessary or desired in order to reduce the pH of the foam.
This is desired in particular when the active ingredient
present in the dosage form is relatively insoluble under
basic conditions, such as, for example, ibuprofen, or with
active ingredients which are unstable under basic
conditions.
A further possibility is to add moisturizers or humectants
to the dosage forms of the invention, in particular foams,
in order to improve the esthetic properties of the dried
foam and in order to reduce the fragility or brittleness of
the dried foam. Examples of such agents are, inter alia,
glycerol, propylene glycol and polyglycerol esters. It is
also possible to add, before or after the drying, surface-
active substances in order to improve the stability of the
foam before or after the drying. Examples of suitable
surface-active substances are, inter alia, substituted
sorbitan derivatives, a.n particular those of the Tween
series (ICT).
The following processes are proposed for the production of
the dosage forms of the invention with improved mouthfeel
and reduced tendency to stick.
Firstly a solution or dispersion which comprises at least
one water-soluble film-forming polymer and at least one
active ingredient is prepared. This solution or dispersion,
which may also be a concentrated solution or viscous
composition, is subsequently foamed by introducing gas or
gas mixture (e.g. air). This can take place by use of a
disperses or of a foam-beating machine, but also by other
methods, e.g. using ultrasound. Suitable gases are, in
particular, also inert gases such as nitrogen, carbon
dioxide or helium, or mixtures thereof.
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In order to stabilize the foams or compositions containing
air bubbles (or containing gas bubbles) which have been
produced in this way, a foam-stabilizing agent is added
before or during the production of foam. Agents suitable
for this purpose, e.g. surfactants, are known to the
skilled worker. Finally, the composition containing air
bubbles or the foam is spread as film or layer on a
suitable substrate and is then dried. Removal of solvent
during the drying causes the foam to solidify to an
aerogel, during which the cavities which have formed
acquire a permanent structure. Wafers with desired surface
dimensions or geometric shapes are obtained by pouring the
foamed coating composition into appropriate molds or by
punching the individual wafers out of a larger-area piece.
The active ingredient-containing drug forms obtained in
this way have the properties and advantages of the
invention. The shape, number and size of the spaces or
cavities produced can be influenced by various process
parameters, e.g. by the nature and concentration of the
polymers, by the viscosity of the polymer composition, by
the control of the foaming process, by the selection of the
foam-stabilizing agents etc.
Another process of the invention for producing said dosage
forms provides, as a modification of the process described
above, for a formation of~the spaces or cavities in the
interior of the polymer matrix to take place by introducing
a hydrophobic solvent which is immiscible with the solvent
used to prepare said solution or dispersion.
In this case, an emulsion which contains the hydrophobic
solvent in the form of finely distributed droplets is
produced. Removal of the solvents during the subsequent
drying leaves droplet- or bubble-shaped cavities behind in
the polymer matrix. In the case of a two-phase system, the
solvent of the internal phase must be removed first.
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A further possibility in a modification of the process
described above is to produce said cavities in such a way
that excipients which form a gas or gases are added to the
polymer- and active ingredient-containing solution or
dispersion, whereby the composition is foamed. This foaming
through evolution of gas can take place either during the
production of the polymer composition or during the coating
of this composition onto the substrate, or not until the
subsequent drying process. Substances or mixtures of
substances suitable for gas formation are known to the
skilled worker. The~foaming can also be brought about by
decompression of a previously dissolved gas. It is possible
to use as gas in particular an inert gas such as nitrogen,
carbon dioxide or helium, or a mixture thereof.
Production of the dosage forms of the invention may
alternatively also start from a melt of the matrix polymer
or polymer mixture. The processing is in principle similar
to that with hot melt coating compositions known in the
prior art.
Gas or a gas mixture is introduced by one of the
aforementioned methods into said polymer melt in order to
cause foaming of the melt. The melt is then spread or
extruded onto a suitable substrate or poured into a mold
and then left to cool and solidify. Processing from the
melt is unsuitable if the intended active ingredient is
unstable or volatile at the melting point of the polymer
melt. It is possible if necessary to add excipients to
reduce the melting point of the polymer melt. It is also
possible in principle to use hot melt coating compositions
known from the prior art as long as they meet the
conditions stated in claim 1.
In a further modification of the production process
described above, the polymer matrix is initially produced
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in the form of a block. The required sheet-like dosage
forms are then removed from the latter by cutting.
The dosage forms of the invention are advantageously
suitable for administering medicaments in the oral cavity
or for rectal, vaginal or intranasal administration. They
can be employed i.n human medicine and in veterinary
medicine.
Production example
111,43 g of distilled water are introduced;
22,38 g of Mowiol 8-88* are added with stirring;
heating of the mixture to 80°C;
stirring (30 min);
cooling to 40°C;
addition of 1,8 g of PEG 400,
addition of 1,8 g of PEG 4000;
homogenization;
addition of aspartame (0,18 g) and flavor (5,58 g);
stirring;
addition of 26,46 g of nicotine hydrogen tartrate;
addition of 1,8 g of silicon dioxide;
stirring (2 h) and foam beating at temperature below 50°C;
spreading;
drying at 60°C (15 min).
* partially hydrolyzed polyvinyl alcohol of low viscosity
(supplied by Clariant)
