Note: Descriptions are shown in the official language in which they were submitted.
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DOSAGE FORM HAVING A SACCHARIDE MATRIX
Technical Field
This invention relates to a non-compressed fast dispersing solid dosage form
suitable for administration of a pharmaceutically active substance and for
preparing a compressed fast dispersing tablet.
Background of the Invention
Allergy is a major health problem in countries where Western lifestyle is
adapted. Furthermore, the prevalence of allergic disease is increasing in
these countries. Although allergy in general may not be considered a life-
threatening disease, asthma annually causes a significant number of deaths.
An exceptional prevalence of about 30% in teenagers conveys a substantial
loss in quality of life, working days and money, and warrants a classification
among major health problems in the Western world.
Allergy is a complex disease. Many factors contribute to the sensitisation
event. Among these is the susceptibility of the individual defined by an as
yet
insufficiently understood interplay between several genes. Another important
factor is allergen exposure above certain thresholds. Several environmental
factors may be important in the sensitisation process including pollution,
childhood infections, parasite infections, intestinal microorganisms, etc.
Once
an individual is sensitised and the allergic immune response established, the
presence of only minute amounts of allergen is efficiently translated into
symptoms.
The natural course of allergic disease is usually accompanied by aggravation
at two levels. Firstly, a progression of symptoms and disease severity, as
well as disease progression, for example from hay fever to asthma.
Secondly, dissemination in offending allergens most often occurs resulting in
allergic multi-reactivity. Chronic inflammation leads to a general weakening
of
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the mucosal defense mechanisms resulting in unspecific irritation and
eventually destruction of the mucosal tissue. Infants may become sensitised
primarily to foods, i.e. milk, resulting in eczema or gastrointestinal
disorders;
. however, most often they outgrow these symptoms spontaneously. These
infants are at risk of developing inhalation allergy later in their lives.
The most important allergen sources are found among the most prevalent
particles of a certain size in the air we breathe. These sources are
remarkably universal and include grass pollens and house dust mite faecal
particles, which together are responsible for approximately 50% of all
allergies. Of global importance are also animal dander, i.e. cat and dog
dander, other pollens, such as mugwort pollens, and micro-fungi, such as
Alternaria. On a regional basis yefi other pollens may dominate, such as birch
pollen in Northern and Central Europe, ragweed in the Eastern and Central
United States, and Japanese cedar pollen in Japan. Insects, i.e. bee and
wasp venoms, and foods each account for approximately 2°/~ of all
allergies.
Allergy, i.e. type 1 hyper-sensitivity, is caused by an inappropriate
immunological reaction to foreign non-pathogenic substances. Important
clinical manifestations of allergy include asthma, hay fever, eczema, and
gastro intestinal disorders. The allergic reaction is prompt and peaks within
20 minutes upon contact with the offending allergen. Furthermore, the
allergic reaction is specific in the sense that a particular individual is
sensitised to particular allergen(s), whereas the individual does not
necessarily show an allergic reaction to other substances known to cause
allergic disease. The allergic phenotype is characterized by a pronounced
inflammation of the mucosa of the target organ and by the presence of
allergen specific antibody of the IgE class in the circulation and on the
surfaced of mast-cells and basophils.
An allergic attack is initiated by the reaction of the foreign allergen with
allergen specific IgE antibodies, when the antibodies are bound to high
affinity IgE specific receptors on the surface of mast-cells and basophils.
The
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mast-cells and basophils contain preformed mediators, i.e. histamine,
tryptase, and other substances, which are released upon cross-linking of two
or more receptor-bound IgE antibodies. IgE antibodies are cross-linked by
the simultaneous binding of one allergen molecule. It therefore follows that a
foreign substance having only one antibody binding epitope does not initiate
an allergic reaction. The cross-linking of receptor bound IgE on the surface
of
mast-cells also leads to release of signaling molecules responsible for the
attraction of eosinophils, allergen specific T-cells, and other types of cells
to
the site of the allergic response. These cells in interplay with allergen, IgE
and effector cells, lead to a renewed flash of symptoms occurring 12-24
hours after allergen encounter (late phase reaction).
20
Allergy disease management comprises diagnosis and treatment including
prophylactic treatments. Diagnosis of allergy is concerned with by the
demonstration of allergen specific IgE and identification of the allergen
source. In many cases a careful anamnesis may be sufficient for the
diagnosis of allergy and for the identification of fihe offending allergen
source
material. Most often, however, the diagnosis is supported by objective
measures, such as skin prick test, blood test, or provocation test.
The fiherapeutic options fall in three major categories. The first opportunity
is
allergen avoidance or reduction of the exposure. Whereas allergen
avoidance is obvious e.g. in the case of food allergens, it may be difficult
or
expensive, as for house dust mite allergens, or it may be impossible, as for
pollen allergens. The second and most widely used therapeutic option is the
prescription of classical symptomatic drugs like anti-histamines and steroids.
Sympfiomatic drugs are safe and efficient; however, they do not alter the
natural cause of the disease, neither do they control the disease
dissemination. The third therapeutic alternative is specific allergy
vaccination
that in most cases reduces or alleviates the allergic symptoms caused by the
allergen in question.
Conventional specific allergy vaccination is a causal treatment for allergic
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disease. It interferes with basic immunological mechanisms resulting in
persistent improvement of the patients' immune status. Thus, the protective
effect of specific allergy vaccination extends beyond the treatment period in
contrast to symptomatic drug treatment. Some patients receiving the
treatment are cured, and in addition, most patients experience a relief in
disease severity and symptoms experienced, or at least an arrest in disease
aggravation. Thus, specific allergy vaccination has preventive effects
reducing the risk of hay fever developing into asthma, and reducing the risk
of developing new sensitivities.
The immunological mechanism underlying successful allergy vaccination is
not known in detail. A specific immune response, such as the production of
antibodies against a particular pathogen, is known as an adaptive immune
response. This response can be distinguished from the innate immune
response, which is an unspecific reaction towards pathogens. An allergy
vaccine is bound to address the adaptive immune response, which includes
cells and molecules with antigen specificity, such as T-cells and the antibody
producing B-cells. B-cells cannot mature into antibody producing cells without
help from T-cells of the corresponding specificity. T-cells that participate
in
the stimulation of allergic immune responses are primarily of the Th2 type.
Establishment of a new balance between Th1 and Th2 cells has been
proposed to be beneficial and central to the immunological mechanism of
specific allergy vaccination. Whether this is brought about by a reduction in
Th2 cells, a shift from Th2 to Th1 cells, or an up-regulation of Th1 cells is
controversial. Recently, regulatory T-cells have been proposed to be
important for the mechanism of allergy vaccination. According to this model
regulatory T-cells, i.e. Th3 or Tr1 cells, down-regulate both Th1 and Th2
cells
of the corresponding antigen specificity. In spite of these ambiguities it is
generally believed that an active vaccine must have the capacity to stimulate
allergen specific T-cells, preferably TH1 cells.
Specific allergy vaccination is, in spite of its virtues, not in widespread
use,
primarily for two reasons. One reason is the inconveniences associated with
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the traditional vaccination programme that comprises repeated vaccinations
i.a. injections over a several months. The other reason is, more importantly,
the risk of allergic side reactions. Ordinary vaccinations against infectious
agents are efficiently performed using a single or a few high dose
5 immunizations. This strategy, however, cannot be used for allergy
vaccination since a pathological immune response is already ongoing.
Conventional specific allergy vaccination is therefore carried out using
multiple subcutaneous immunizations applied over an extended time period.
The course is divided in two phases, the up dosing and the maintenance
phase. In the up dosing phase increasing doses are applied, typically over a
16-week period, starting with minute doses. When the recommended
maintenance dose is reached, this dose is applied for the maintenance
phase, typically with injections every six weeks. Following each injection the
patient must remain under medical attendance for 30 minutes due to the risk
of anaphylactic side reactions, which in principle although exfiremely rare
could be life-threatening. In addition, the clinic should be equipped to
support
emergency treatment. There is no doubt that a vaccine based on a different
route of admin'Lstration would eliminate or reduce the risk for allergic side
reactions inherent in the current subcutaneous based vaccine as well as
would facilitate a more widespread use, possibly even enabling self
vaccination at home.
Attempts to improve vaccines for specific allergy vaccination have been
performed for over 30 years and include multifarious approaches. Several
approaches nave addressed the allergen itself through modification of the
IgE reactivity. Others have addressed this route of administration.
The immune system is accessible through the oral cavity and sublingual
administration of allergens is a known route of administration.
Conventionally allergy vaccine using the oromucosal route consists of the up
to daily dosing of a solution of the allergen. In comparison, the therapeutic
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(accumulated) maintenance doses given exceeded the maintenance of the
comparable subcutaneous dose by a factor 5-500. Obvious drawbacks of this
dosage form and route of administration are the problems associated with
accurate and uniform self administration of the correct dose by the patient
(several drops may have to be given, uniformity of the individual drops,
application site accuracy, etc.). There is additionally a need to refrigerate
the
drug and include preservatives in the formulation.
Netien et al.: "Galenica 16 - Medicaments homeopathiques" ed. 2, 1986,
pages 77-99 discloses a liquid solution impregnated onto a solid particulate
(granules) or conventional compressed tablets of lactose, saccharose or a
mixtures of these for sublinquai administration of medicaments such as
allergens. However these dosage forms are associated with serious
drawbacks, such as the impregnation procedure.
DD-A-0 107 208 discloses a process for preparing a conventional
compressed tablet containing an allergen. Upon administration the tablet is
dissolved by the saliva and the allergen is then absorbed through the mucosa
of the oral cavity. The formulation contains a water insoluble excipient,
namely talcum as well as parafFin and fatty acids which is not desirable since
it will leave an unpleasant remnant in the mouth of the patient. Moreover, the
friction during the tabletting process may be detrimental to the physical
stability of the allergens.
EP 278 877 discloses a pharmaceutical composition for sublingual use,
where a solid support. e.g. saccharose / lactose, is coated with a solution of
an allergen. The resulting formulation is alleged to disintegrate rapidly, but
not instantaneously. However, there is no disclosure of how to achieve the
objective. Moreover, the formulation contains reducing sugars in the form of
lactose, which are prone to react with allergens.
In order to ensure that as much as possible of an administered dose of a
certain allergen is presented to the mucosa of the oral cavity and
additionally
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that the contact time of the disintegrated product with the mucosa is
maximised, it is very important that the dosage form disintegrates
instantaneously upon contact with the saliva of the oral cavity. Fast
dispersing solid dosage forms, which readily release the active ingredient in
the oral cavity are known in the art.
U.S. patent No 4,371,516 discloses pharmaceutical dosage forms containing
active ingredients, which disintegrate rapidly in water. The pharmaceutical
dosage forms comprise an open matrix network of carrier material, which
disintegrate within 10 seconds.
A freeze-dried fish gelatine based carrier as disclosed in WO 00/61117 is
designed to release the active ingredient instantaneously upon contact with
saliva when administered in the oral cavity. As active ingredient a vaccine
against hayfever is mentioned.
A freeze-dried modified starch carrier as disclosed in WO 00/44351 is
designed to release the active ingredient instantaneously upon contact with
saliva when administered in the oral cavity. As active ingredient a vaccine
against hayfever is mentioned. The modified starch carrier may be a dextrin
and a pre-gelatinized starch.
WO 99/21579 discloses a fast-dispersing dosage form comprising a vaccine
and an adjuvant for oral use.
WO 02/13858 discloses fast dissolving pharmaceutical composition
containing vaccines in the form of a fast dissolving "cake" for oral use. The
object of WO 02/13858 appears to be to provide viral or bacterial vaccines
that will stay intact in the gastrointestinal tract. This is achieved by
protecting
the antigen against the acidic content of the stomach by incorporating
antacids such as calcium carbonate into the cake.
WO 00/51568 discloses a fast-disintegrating compressed low friability tablet
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that is designed to dissolve in the mouth in contact with saliva in less than
30
seconds forming an easy-to-swallow suspension.
US-A-5,648,093 discloses a fast dispersing non-compressed solid dosage
form. In a specific example, a dosage form composed of maltodextrin,
mannitol and xanthan gum is disclosed.
WO 91/09591 (Example 25) describes the preparation of a placebo carrier
matrix by solid-state dissolution, wherein the matrix is composed of
maltodextrin (DE10), mannitol and xanthan gum.
US-B2-6 337 082 describes a saccharide-based matrix for use in food
products comprising maltodextrin having a DE of less than 40, preferably
between 20 and 40 and alternatively between 10 and 20, a gelling agent and
a sugar. The gelling agent may e.g. be xanthan gum or gelatine. Sorbitol is
mentioned in a long list of suitable sugars. The matrix is stated to be
instantaneously dispersible in water to form a suspension. The matrix is
formed in a process involving simultaneous flash heating and applied
physical force. The resulting matrix has the form of particles, chips, flakes
or
spicules. The Examples mention a specific composition of maltodextrin
having a DE of 36, sorbitol and a food ingredient, which is spun to form a
matrix of a white, narrow flake.
WO 00/57856 discloses a fast-dispersing dosage form pharmaceutical for
administration upon contact with the buccal membrane, the dosage form
comprising between 50 % and 99 % of a carrier and possibly a diluent. As
carrier maltodextrin having a DE of between 3 and 50 is mentioned from a
long list of compounds. Sorbitol is mentioned as diluent from a long list of
compounds.
Summary of the invention
The present invention relates i.a. to the following:
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A non-compressed fast-dispersing solid dosage form suitable for oromucosal
administration of a pharmaceutically active substance comprising
(a) a first matrix forming agent in the form of maltodextrin having a dextrose
equivalent (DE) of between 1 and 20,
(b) a second matrix forming agent in the form of sorbitol, and
(c) the active substance.
A dosage form according to the invention comprising one or more further
matrix forming agents.
A dosage form according to the invention, wherein the further matrix forming
agent is a mono-, di- or tri-saccharide.
A dosage form according to the invention, wherein the further matrix forming
agent is mannitol.
A dosage form according to the invention further comprising polyethylene
glycol (PEG).
A dosage form according to the invention, wherein maltodextrin is present in
an amount of 3-40 % (w/w), preferably 10-35 (w/w) and more preferably 15-
% (w/w) of the dosing solution.
25 A dosage form according to the invention, wherein mannitol is present in an
amount of 1-20 % (w/w), preferably 2-10 % (w/w) and more preferably 3-6
(w/w) of the dosing solution.
A dosage form according to the invention, wherein sorbitol is present in an
amount of 0.01-10 % (w/w), preferably 0.05-5 % (w/w) and more preferably
0.1-2 % (w/w) of the dosing solution.
A dosage form according to the invention, wherein PEG is present in an
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amount of 1-20 % (w/w), preferably 2-15 % (w/w) and more preferably 3-10
(w/w) of the dosing solution.
A dosage form according to the invention, wherein the active substance is an
5 allergen.
The present invention is based on the surprising finding that it is possible
to
use maltodextrin as primary matrix forming agent in a fast-dispersing non-
compressed dosage form instead of conventional primary matrix forming
10 agents, such as gelatine and starch. Maltodextrin has the advantage over
starch that it dissolves or disperses more quickly, as maltodextrin is partly
hydrolysed. At the same time, it has surprisingly been found that non-
compressed solid dosage forms using maltodextrin as matrix forming agent
has sufficient mechanical strength to remain stable and intact during
manufacture, packaging, transport, handling and storage so as to avoid
degradation of active substance and release of active substance from fihe
dosage form, which is highly undesirable for some active substances, such
as allergens.
Furthermore, it has surprisingly been shown that sorbitol, even in very small
contents, strongly increases the mechanical strength of the dosage form.
Detailed description of the invention
A non-compressed fast dispersing solid dosage form, which is designed to
release the active ingredient almost instantaneously in the oral cavity on
contact with saliva is very suitable for the delivery of the allergens to the
mucosa oromucosally. However, a priori the use of this particular dosage
form for allergens is associated with severe problems. This type of solid
dosage form is namely characterized by a low mechanical strength compared
to compressed tablets due to the inherent nature of the non-compressed
matrix, which is almost wafer-like and fragile. This may result in the release
of residual particles containing the allergen during handling of the dosage
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form by the patient. This is especially detrimental when the active ingredient
is an allergen, because the allergen can elicit an allergic reaction in a
disposed person or induce an allergic reaction, that sensitisation or allergic
response being dose dependent. Maximum allowable levels for
environmental contamination in the form of e.g. allergen in dust have been
proposed depending on the allergen in question as low as 2 micro gram
major allergen per gram house dust. (Allergy. Principles and practice (1993,
4. ed.), Mosby-Year book, Vol. I page 520).
Such non-compressed fast dispersing solid dosage forms, which are
manufactured by removal of a liquid from a solidified system comprising
matrix forming agents, active ingredient and other suitable excipients may be
manufactured in situ.
Due to the in situ manufacturing process, i.e. removal of the solvent from a
solidified system of the active ingredient and the matrix forming excipients
in
the final container, i.e. blister packs, it is not possible to coat the dosage
form
in order to seal it and thus preventing the release of residues from the
dosage form. Moreover, coating the dosage form is not possible, because it
would jeopardize the instantaneous release properties of the dosage form.
Thus, there exists a need for a fast dispersing solid dosage form containing
allergens, which quickly releases the allergen in the oral cavity, and where
the dosage form at the same time has such a mechanical robustness, so
ideally no residues will be released from the dosage form to the environment
during handling of the dosage form by the patient.
Further, there is the need for a fast dispersing solid dosage forms containing
allergens to have sufficient chemical stability of the active ingredients to
allow
the manufacture, transportation, storage and especially patient handling.
It has now surprisingly been found that it is indeed possible to manufacture a
low friable non-compressed fast dispersing solid dosage form containing
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allergens, which is sufficiently robust and does not release hazardous
amounts of residue upon handling by the patient. Moreover, it has
surprisingly been found that these formulations are indeed stable at room
temperature. This finding has significant importance for the handling
procedures of the final product. Cold storage at the manufacturing plant,
during transport or during storage at the pharmacy is often associated with
high cost, since the cooling facilities have to be closely monitored and it is
also very expensive to invest in reliable cooling facilities. Moreover, with
respect to compliance of the patient, it is also preferable that the dosage
form
can be stored at room temperature. The European Pharmacopeia
monograph for Allergen Products states that the moisture levels should not
exceed 5 % for freeze-dried products (i.e. allergen extracts in vials). It has
surprisingly been found that even the dosage forms according to the
invention having water content above the required maximum level of 5% are
stable at room temperature. Without being bound to theory it may be
explained by fihe fact that the excipients of the fast dispersing solid dosage
form binds the remaining water in the dosage form and reduces the water
activity of the allergen vaccine dosage formulation. Hence, by reducing the
water activity of the formulation, it is possible to obtain a stable
formulation
with no degradation of the allergen, even though the water content is higher
than maximum level of 5%, which is prescribed for allergen extracts in vials.
Stability of the solid dosage form in order to ensure a sufficient shelf life
of
the final product may me measured with reference to physical and chemical
properties of the solid dosage form or its individual constituents.
Water activity is one important factor contributing to the shelf life of a
product.
It is well known that the water activity of a product affects growths of
bacteria
as well as the stability, the potency and consistency of pharmaceuticals. Also
protein stability is influenced significantly by water activity due to their
relatively fragile nature. Most proteins must maintain conformation to remain
active, Maintaining low water activity levels helps to prevent or entice
conformational changes, which subsequently is important to ensure that a
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protein in the form of an allergen is stable. Also hydrolytic degradation of
proteins whether caused by enzymes or not is affected by the water activity.
Water activity measurements are carried out by using methods known to the
person skilled in the art for example chilled mirror dew point technology,
relative humidity with sensors that change electrical resistance or
capacitance or using a lithium chloride electrode.
The water. activity of a solid dosage form preferable does not exceed 25
and preferably be between 0.1 % - 20%, more preferably between 0.5 - 15
%, more preferably 2 - 8%, most preferably between 4-7 %.
The water content of a solid dosage form determined according to the
method described in example 1 does preferably not exceed 25 % and
preferably be between 0.1 % - 20%, more preferably between 0.5 - 15 %,
more preferably 2 - 8%, most preferably between 4-~ %.
Several laboratory tests are available for characterising an allergen. The
most widely used techniques are sodium dodecyl sulphate polyacrylamide
gel electrophoresis (SDS-PAGE), isoelectric focusing (IEF), crossed
immunoelectrophoresis (CIE) and Rocket Immuno Electrophoresis (RIE). The
quantification of individual allergens may be performed by a variety of
quantitative immunoelectrophoretic techniques (QIE), Radial immune
Diffusion (RIE) or by enzyme-linked immunosorbent assays (ELISA). The
determination of total allergenic potency is most frequently performed by
radio allergosorbent test (RAST), (LIA) or related techniques. EL~ISA-based
techniques may also be used.
Guidance to the normally applied acceptable limit for test measuring
biopotency are found e.g. in Note for Guidance on Allergen Product ; The
European Agency for the Evaluation of Meicinal Product,
CPMP BWP 243 96.
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Preferably for the purpose of this invention the stability of the active
ingredient i.a. the allergen is assessed by means of potency measurements
of the allergen like total allergen activity and major allergen content.
The ~"initial allergenic activity" or the "initial content of at least one
major
allergens" of a solid dosage form means the value as after the completion of
the manufacturing of the solid dosage form.
Loss in total allergen activity according the method described in example 1
should preferably be less than 50 % of the total initial activity, more
preferably less than 30 % of the total initial activity , even more preferably
be
less than 20 % of the total initial activity, most preferably less than 15 %
of
the total initial activity.
The classification of an allergen as a major allergen can be subject to
several
tesfi. An allergens are commonly classified as major allergen if at least
25°/~
of the patients shows strong IgE binding (score 3) and at least moderate
binding (score 2) from 50% of the patients, the binding being determined by
an CRIE (CRIE Strong binding i.e. visible IgE-binding on a x-ray film after
one day, CRIE Moderat binding i.e. binding after 3 days, CRIE Weak binding
i.e. binding after 10 loge). Strong IgE binding from at least 10°/~ of
the
patients classifies the allergen as an Intermediate allergen and clearly
specific binding from less than 10% of the patients gives a Minor allergen.
Other methods may also be used in determining the IgE binding of for
instance IgE-blots.
Loss in the allergen content of at least one major allergen according to the
method described in example 1 is preferably less than 50 % of the total
initial
content, more preferably less than 30 % of the total initial content, even
more
preferably less than 20 % of the total initial content, most preferably less
than
15 % of the initial content.
In one embodiment of the solid allergen dosage form the loss in total allergen
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activity according the method described in example 1 is less than 50 % of the
total initial activity.
In another embodiment of the solid allergen dosage the loss allergen content
5 of at least one major allergen according to the method described in example
1 is less than 50 % of the initial content.
The dosage form of the invention is preferably stable in the sense that it
does
not significantly change after manufacture with respect to physical and
10 chemical properties e.g. potency of the allergen, mechanical robustness and
organoleptical properties in order to ensure a sufficient shelf life of the
final
product.
Thus, the stability of the solid dosage form is preferably assessed by
15 additional parameters, such as mechanical robustness like friability,
tensile
strength, peak load to fracture, stability of physical properties i.a. the
dispersion time and stability of organoleptical properties like visual
appearance of the dosage form.
These can be evaluated by e.g. measurements of Peak load to fracture or
tensile strength of the solid dosage forms of the current invention. ~4s it is
apparent from the equation from which the tensile strength can be calculated,
the tensile strength value obtained depend of a number of parameter, which
are subject to variation e.g. thickness or diameter of the solid dosage form
and will contribute to the variation of value. Therefore Peak load to fracture
is
believed to be a even more accurate parameter for evaluation of the
robustness of the solid dosage units of the current invention
In order to ensure that the solid dosage form is sufficient robust during
storage and when handled by the patient, the dosage form needs to have a
certain resistance to external force, but at the same time ensure that the
solid
dosage form disintegrates quickly in the mouth.
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In a further embodiment of the current invention the solid dosage form
preferably has a tensile strength less than 1.1 N/mm2, more preferably less
than 0.8 N/mm2. Typically, the dosage form has a tensile strength of
between 0.2 and 0.5 N/mm2. The lower the tensile strength is, the lower the
mechanical strength and stability of the dosage form, and the faster it
disperses.
Preferably fast dispersing dosage form disintegrates instantaneously or
quickly in the mouth upon contact with the saliva in order to ensure maximum
exposure of allergen to immune competent tissue of the mucosa before
swallowing. In a preferred embodiment the solid dosage form disintegrates in
less than about 90 seconds, preferably in less than 60 seconds, preferably in
less than 30 seconds, more preferably in less than 20, more preferably in 15
seconds, even more preferably in less than 10 seconds in the oral cavity,
even more preferably in less than 5, most preferably in less than about 2 sec.
In a preferred embodiment of the invenfiion, the compositions of the invention
are fast dispersing solid dosage forms comprising a solid network of the
allergen and any water-soluble or water-dispersible matrix. The network is
obtained by subliming solvent from a composition in the solid state, the
composition comprising a solution of the allergen and the matrix. fVlore
preferably the network is obtained by lyophilization.
Excipients
In a preferred embodiment of the invenfiion, the dosage form further
comprising one or more excipients in addition the matrix forming agent.
Pharmaceutically acceptable excipients forming part of the matrix in the fast
dispersing solid dosage form according to invention are suitable excipients
such as adjuvants, antacids, diluents, enhancers, mucoadhesive agents,
flavouring agents, taste masking agents, preservatives, antioxidants,
surfactants, viscosity enhancers, colouring agents, pH modifiers, sweeteners
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etc. These excipients are all selected in accordance with conventional
pharmaceutical practice in a manner understood by the persons skilled in the
art of formulating allergen vaccines.
In a preferred embodiment of the invention, the dosage form contains a
protein stabilizing agent. Examples of protein stabilising agents are
polyethylene glycols (PEG), e.g. PEG300, PEG400, PEG600, PEG1000,
PEG1500, PEG3000, PEG3050, PEG4000, PEH6000, PEG20000 and
PEG35000; amino acids, such as glycin, alanine, arginine; mono-, di and tri-
saccharides, such as trehalose and sucrose; polyvinylalcohol (PVA);
polyoxyethylene sorbitan fatty acid esters (polysorbates, tweens or span);
human serum albumin (HSA); bovine serum albumin (BSA). Preferably, PEG
is used as protein stabilising agent. In addition to being a protein
stabiliser,
PEG is believed to confer the property of elasticity to the matrix of the
dosage
form.
Suitable colouring agents include red, black and yellow iron oxides and FD ~
G dyes such as FD ~ G blue No. 2 and FD & G red No. 40. Suitable
flavouring agents include mint, raspberry, liquorice, orange, lemon,
grapefruit, caramel, vanilla, cherry and grape flavours and combination of
these. Suitable pH modifiers include citric acid, tartaric acid, phosphoric
acid,
hydrochloric acid and malefic acid. Suitable sweeteners include aspartame,
acesulfame K and thaumatic. Suitable taste-masking agents include sodium
bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds,
adsorbates or microencapsulated actives.
Adjuvants are normally used to enhance the absorption of the allergen as
well as to enhance the immune-stimulating properties of the allergen.
In one embodiment of the invention at least one adjuvant is incorporated into
the dosage form according to the invention. Examples of suitable adjuvants
are aluminium salts, non-toxic bacterial fragments, cytokines, chlorea toxin
(and detoxified fractions thereof), chitosan, homologous heat-labile of E.coli
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(and detoxified fractions thereof), saponins, bacterial products such as
lipopoly-saccharides (LPS) and muramyl dipeptide (MDP), liposomes, CpG
(immunostimulatory DNA sequences), lactide/glycolide homo ( copolymers in
the form of microparticular polymers etc. The use of adjuvants in allergen
vaccines are often reasoned by the fact the allergens in question are not able
to penetrate the barrier to be passed. The adjuvants thus may serve as
absorption enhancing agents or they may act as immunostimulants. The use
of adjuvants may, however, be associated with serious draw backs such as
unintended stimulation of various mechanisms of the immune response,
systemic lupus erythematosus or affecting the barrier capabilities of the
mucosal membranes and thus allowing the passage of hazardous
substances. Further from an industrial point of view addition of an adjuvant
further constitute further manufacturing and material cost besides the large
demand for documentation in respect to drug registration.
In another preferred embodiment of the invention the fast dispersing solid
dosage form according to the invention does not comprise an adjuvant.
It has also surprisingly been found that it is not necessary to incorporate an
adjuvant into the fast dispersing solid dosage form in order to enhance the
immune-stimulating properties of the allergen in question i.e. that the solid
dosage form is capable of raising a specific immune response.
The non-compressed fast dispersing solid dosage form according to the
invention may be mucoadhesive to some extent in itself, however in a
preferred embodiment of the invention, it may be necessary to further add
mucoadhesive excipients to said dosage form in order to increase the contact
time of the dosage form with the mucosa of the oral cavity. Suitable
mucoadhesive excipients are polyacrylic polymers such as carbomer and
carbomer derivatives; cellulose derivatives such as
hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcelllulose
and sodium carboxymethylcellulose; natural polymers such as gelatine,
sodium alginate, pectin and glycerol.
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Matrix forming agent
In a preferred embodiment of the invention, maltodextrin has a DE of
between 1 and 15, more preferably between 1 and 10.
In a preferred embodiment of the invention the further matrix forming agent is
a mono-, di- or tri-saccharide. Examples of mono-, di- and tri-saccharides are
mannose, glucose, galactose, mannitol, mannose, galactitol, erythritol,
inositol, threitol, maltitol, trehalose, sucrose, maltose, maltrotriose,
lactose,
palatinose and lactulose. Preferred mono-, di- and tri-saccharide are
mannose and mannitol.
In a preferred embodiment of the dosage form of the invention, the further
matrix forming agent is mannitol.
Other matrix forming agents suitable for use according to the present
invention include substances derived from animal or vegetable proteins, such
as gelatines, soy, wheat and psyllium seed proteins; gums, such as acacia,
guar, agar and xanthan; polysaccarides, such as starch and modified starch;
cyclic sugars such as cyclodextrin; alginates; carboxymethylcellulose;
carrageenans; dextrans; pectins; synthetic polymers, such as
polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes
such as gelatine-acacia complexes.
Other matrix forming agents suitable for use according to the present
invention inorganic salts such as sodium phosphate, sodium chloride and
aluminium silicates; and amino acids having from 2 to 12 carbon atoms such
as a glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L
isoleucine, L-leucine and L-phenylalanine.
As mentioned above the present invention has provided a possibility of
producing fast dispersing non-compressed dosage forms using maltodextrin
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as primary matrix forming agent and sorbitol as secondary matrix forming
agent.
Furthermore, the present invention has provided a possibility of producing
5 fast dispersing non-compressed dosage forms with a matrix composed of
maltodextrin, sorbitol and mono-, di- and trisaccharides. Thus, in another
preferred embodiment of the invention, the matrix is free of other matrix
forming agents than maltodextrin, sorbitol and mono-, di- and trisaccharides.
In particular, the matrix is preferably free of polymeric matrix forming
agents,
10 and more specifically the matrix is preferably free of gelatines and/or
starch
and/or gums.
The total dry matter content of the dosing solution is preferably above 20
(w/w), more preferably above 30 % (w/w), more preferably above 40 % (w/w),
15 more preferably above 50 % (w/w) and most preferably above 60 % (w/w).
The total dry matter content of the dosing solution will depend on the
dimensions of the tablet to be produced.
Pharmaceutically active substance
The pharmaceutically active substance used in the dosage form of the
invention may be any active substance, which is capable of being
administered through the oromucosal route. Oromucosal administration is
particularly relevant, when a quick administration is desired and/or where
administration via the intestinal mucosa is difficult, e.g. because of
difficulties
in the transport of the active substance across the mucosa and/or because of
degradation of the active substance through the passage of the gastro-
intestinal system. Administration via the oromucosal route is e.g. relevant
for
proteins.
Examples of suitable active substances include, but are not limited to:
Analgesics and anti-inflammatory agents: aloxiprin, auranofm, azapropazone,
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benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcim, flurbiprofen,
ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid,
nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone,
piroxicam, sulindac.
Anthelmintics: albendazole, bephenium hydroxynaphthoate, cambendazole,
dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel
embonate, praziquantel, pyrantel embonate, thiabendazole.
Anti-arrhythmic agents: amiodarone HCI, disopyramide, flecainide acefiate,
quinidine sulphate.
Anti-bacterial agents: benethamine penicillin, cinoxacin, ciprofloxacin HCI,
clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline,
erythromycin, ethionamide, imipenem, nalidixic acid, nitrofuranfioin,
rifampicin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine,
sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole,
sulphapyridine, tetracycline, trimethoprim.
Anti-coagulants: dicoumarol, dipyridamole, nicoumalone, phenindione.
Anti-depressants: amoxapine, ciclazindol, maprotiline HCI, mianserin HCI,
nortriptyline HCI, trazodone HC1, trimipramine maleate.
Anti-diabetics: acetohexamide, chlorpropamide, glibenclamide, gliclazide,
glipizide, tolazamide, tolbutamide.
Anti-epileptics: beclamide, carbamazepine, clonazepam, ethotoin, methoin,
methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione,
phenacemide, phenobarbitone, phenytoin, phensuximide, primidone,
sulthiame, valproic acid.
Anti-fungal agents: amphotericin, butoconazole nitrate, clotrimazole,
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econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole,
ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate,
terbinafine HC1, terconazole, tioconazole, undecenoic acid.
Anti-gout agents: allopurinol, probenecid, sulphinpyrazone.
Anti-hypertensive agents: amlodipine, benidipine, darodipine, dilitazem HC1,
diazoxide, felodipine, guanabenz acetate, indoramin, isradipine, minoxidil,
nicardipine HC1, nifedipine, nimodipine, phenoxybenzamine HC1, prazosin
HCL, reserpine, terazosin HC1.
Anti-malarials: amodiaquine, chloroquine, chlorproguanii HC1, halofantrine
HC1, mefloquine HC1, proguanil HC1, pyrimethamine, quinine sulphate.
Anti-migraine agents: dihydroergotamine mesylate, ergotamine tartrate,
methysergide maleate, pizotifen maleate, sumatriptan sueeinate.
Anti-muscarinic agents: atropine, benzhexol HC1, biperiden, ethopropazine
HCI, hyoscine butyl bromide, hyoscyamine, mepenzolate bromide,
orphenadrine, oxyphencylcimine HC1, tropicamide.
Anti-neoplastic agents and Immunosuppressants: aminoglutethimide,
amsacrine, azathioprine, busulphan, chlorambucil, cyclosporin, dacarbazine,
estramustine, etoposide, lomustine, melphalan, mercaptopurine,
methotrexate, mitomycin, mitotane, mitozantrone, procarbazine HC1,
tamoxifen citrate, testolactone.
Anti-protazoal agents: benznidazole, clioquinol, decoquinate,
diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furzolidone,
metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole.
Anti-thyroid agents: carbimazole, propylthiouracil.
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Anxiolytic, sedatives, hypnotics and neuroleptics: alprazolam,
amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol,
brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole,
chlorpromazine, clobazam, clotiazepam, clozapine, diazepam, droperidol,
ethinamate, flunanisone, flunitrazepam, fluopromazine, flupenthixol
decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam,
lormetazepam, medazepam, meprobamate, methaqualone, midazolam,
nitrazepam, oxazepam, pentobarbitone, perphenazine pimozide,
prochlorperazine, sulpiride, temazepam, thioridazine, triazolam, zopiclone.
(3-blockers: acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol,
oxprenolol, pindolol, propranolol.
Cardiac Inotropic agents: amrinone, digitoxin, digoxin, enoximone, lanatoside
C, medigoxin.
Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone
acetate, desoxymethasone, dexamethasone, fludrocortisone acetate,
flunisolide, flucortolone, fluticasone propionate, hydrocortisone,
methylprednisolone, prednisolone, prednisone, triamcinolone.
Diuretics: acetazolamide, amiloride, bendrofluazide, bumetanide,
chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone,
spironolactone, triamterene.
Enzymes:
Anti-parkinsonian agents: bromocriptine mesylate, lysuride maleate.
Gastro-intestinal agents: bisacodyl, cimetidine, cisapride, diphenoxylate HCI,
domperidone, famotidine, loperamide, mesalazine, nizatidine, omeprazole,
ondansetron HCL, ranitidine HCI, sulphasalazine.
Histamine H,-Receptor Antagonists: acrivastine, astemizole, cinnarizine,
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cyclizine, cyproheptadine HCI, dimenhydrinate, flunarizine HCI, meclozine
HCI, oxatomide, terfenadine, triprolidine.
Lipid regulating agents: bezafibrate, clofibrate, fenofibrate, gemfibrozil,
probucol.
Local anaesthetics:
Neuro-muscular agents: pyridostigmine.
Nitrates and other anti-anginal agents: amyl nitrate, glyceryl trinitrate,
isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate.
Nutritional agents: betacarotene, vitamin A, vitamin B2, vitamin D, vitamin E,
vitamin K.
Opioid analgesics: codeine, dexfiropropyoxyphene, diamorphine,
dihydrocodeine, meptazinol, methadone, morphine, nalbuphine, pentazocine.
Oral vaccines: Vaccines designed to prevent or reduce the symptoms of
diseases of which the following is a representative but not exclusive list:
Influenza, Tuberculosis, Meningitis, Hepatitis, !S!lhooping Cough, Polio,
Tetanus, Diphtheria, Malaria, Cholera, Herpes, Typhoid, HIV, AIDS, Measles,
Lyme disease, Travellers'Diarrhea, Hepatitis A, B and C, Otitis Media,
Dengue Fever, Rabies, Parainfluenza, Rubella, Yellow Fever, Dysentery,
Legionnaires Disease, Toxoplasmosis, Q-Fever, Haemorrhegic Fever,
Argentina Haemorrhagic Fever, Caries, Chagas Disease, Urinary Tract
Infection caused by E. coli, Pneumoccoccal Disease, Mumps, and
Chikungunya.
Vaccines to prevent or reduce the symptoms of other disease syndromes of
which the following is a representative but not exclusive list of causative
organisms:
Vibrio species, Salmonella species, Bordetella species, Haemophilus
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species, Toxoplasmosis gondii, Cytomegalovirus, Chiamydia species,
Streptococcal species, Norwalk Virus, Escherischia coli, Helicobacter pylori,
Rotavirus, Neisseria gonorrhae, Neisseria meningiditis, Adenovirus, Epstein
Barr Virus, Japanese Encephalitis Virus, Pneumocystis carini, Herpes
5 simplex, Clostridia species, Respiratory Syncytial Virus, Klebsielia
species,
Shigella species, Pseudomonas aeruginosa, Parvovirus, Campylobacter
species, Rickettsia species, Varicella zoster, Yersinia species, Ross River
Virus, J. C. Virus, Rhodococcus equi, Moraxella catarrhalis, Borrelia
burgdorferi and Pasteurella haemolytica.
Vaccines directed to non-infections immuno-modulated disease conditions
such as topical and systematic allergic conditions such as Hayfever, Asthma,
Rheumatoid Arthritis and Carcinomas.
Vaccines for veterinary use include those directed to Coccidiosis, Newcastle
Disease, Enzoofiic pneumonia, Feline leukaemia, Atrophic rhinitis, Erysipelas,
Foot and Mouth disease, Swine, pneumonia, and other disease conditions
and other infections and auto-immune disease conditions affecting
companion and farm animals.
Proteins, peptides and recombinant drugs: insulin (hexameric/dimeric/-
monomeric forms), glucagon, growth hormone (somatotropin), polypeptides
or their derivatives, (preferably with a molecular weight from 1000 to
300,000), calcitonins and synthetic modifications thereof, enkephalins,
interferons (especially Alpha-2 interferon for treatment of common colds),
LHRH and analogues (nafarelin, buserelin, zolidex), GHRH (growth hormone
releasing hormone), secretin, bradykin antagonists, GRF (growth releasing
factor), THF, TRH (thyrotropin releasing hormone), ACTH analogues, IGF
(insulin like growth factors), CGRP (calcitonin gene related peptide), atrial
natriurectic peptide, vasopressin and analogues (DDAVP, lypressin), factor
VIII, G-CSF (granulocyte-colony stimulating factor), EPO (erythropoitin).
Sex hormones: clomiphene citrate, danazol, ethinyloestradiol,
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medroxyprogesterone acetate, mestrano(, methyltestosterone,
norethisterone, norgestrel, oestradiol, conjugated oestrogens, progesterone,
stanozolol, stiboestrol, testosterone, tibolone.
Spermicides: nonoxynol 9.
Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine,
mazindol, pemoline.
In a preferred embodiment of the invention the pharmaceutically active
substance is an allergen. In the rest of this section and in most other parts
of
the description the invention is described with respect to this embodiment of
the invention.
According to the invention an allergen vaccine is provided in a fast
dispersing
solid dosage form, which rapidly dissolves in the oral cavity on confiact
wifih
saliva, hence bringing the allergen in close contact with the immunological
relevant tissue of the mucosa and allowing the allergen to address these. In a
preferred embodiment of the invention the allergen according to the present
invention is any naturally occurring protein that has been reported to induce
allergic, i.e. IgE mediated reactions upon their repeated exposure to an
individual. Examples of naturally occurring allergens include pollen allergens
(free-, herb, weed-, and grass pollen allergens), insect allergens (inhalant,
saliva and venom allergens, e.g. mite allergens, cockroach and midges
allergens, hymenopthera venom allergens), animal hair and dandruff
allergens (from e.g. dog, cat, horse, rat, mouse etc.), and food allergens.
Important pollen allergens from trees, grasses and herbs are such originating
from the taxonomic orders of Fagales, Oleales, Pinales and platanaceae
including i.a. birch (Betula), alder (Alnus), hazel (Corylus), hornbeam
(Carpinus) and olive (Olea), cedar (Cryptomeria and Juniperus), Plane tree
(Platanus), the order of Poales including i.a. grasses of the genera Lolium,
Phleum, Poa, Cynodon, Dactylis, Holcus, Phalaris, Secale, and Sorghum, the
orders of Asterales and Urticales including i.a. herbs of the genera Ambrosia,
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Artemisia, and Parietaria . Other important inhalation allergens are those
from house dust mites of the genus Dermatophagoides and Euroglyphus,
storage mite e.g Lepidoglyphys, Glycyphagus and Tyrophagus, those from
cockroaches, midges and fleas e.g. Blatella, Periplaneta, Chironomus and
Ctenocepphalides, and those from mammals such as cat, dog and horse,
venom allergens including such originating from stinging or biting insects
such as those from the taxonomic order of Hymenoptera including bees
(superfamily Apidae), wasps (superfamily Vespidea), and ants (superfamily
Formicoidae). Important inhalation allergens from fungi are i.a. such
originating from the genera Alternaria and Cladosporium.
In a more preferred embodiment of the invention the allergen is Bet v 1, Aln g
l,Cora1 andCarb1,Queal,Cryj1,Cryj2,Cupa1,Cups1,Juna1,
Jun a2,juna3,Olee1 ,Ligv1,PIa11,PIaa2,Amba1,Amba2,Ambt5,
Art v 1, Art v 2 Par j 1 , Par j 2, Par j 3, Sal k 1, Ave a 1, Cyn d 1, Cyn d
7,
Dac g 1, Fes p 1, Hol I 1, Lol p 1 and 5, Pha a 1, Pas n 1, Phl p 1, Phl p 5,
Phl p 6, Poa p 1, Poa p 5, Sec c 1, Sec c 5, Sor h 1, Der f 1 , Der f 2, Der p
1, Der p 2, , Der p 7, Der m 1, Eur m 2, Gly d 1, Lep d 2, Blo t 1, Tyr p 2,
Bla
g 1, Bla g 2, Per a 1, Fel d 1, Can f 1, Can f 2 , Bos d 2, Equ c 1, Equ c 2,
Equ c 3 , Mus m 1, Rat n 1, Apis m 1, Api m 2 , Ves v 1, Ves v 2, Ves v 5,
Dol m 1, Dil m 2, Dol m 5, Pol a 1, Pol a 2, Pol a 5, Sol i 1, Sol i 2, Sol i
3
and Sol i 4, Alt a 1, Cla h 1, Asp f 1, Bos d 4, Mal d 1, Gly m 1, Gly m 2,
Gly
m 3, Ara h 1, Ara h 2, Ara h 3, Ara h 4, Ara h 5 or shufflant hybrids from
Molecular Breeding of any of these.
In the most preferred embodiment of the invention the allergen is grass
pollen allergen or a dust mite allergen or a ragweed allergen or a cedar
pollen or a cat allergen or birch allergen.
In yet another embodiment of the invention the fast dispersing solid dosage
form comprises at least two different types of allergens either originating
from
the same allergic source or originating from different allergenic sources e.g.
grass group 1 and grass group 5 allergens or mite group 1 and group 2
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allergens from different mite and grass species respectively, weed antigens
like short and giant ragweed allergens, different fungis allergens like
alternaria and cladosporium, tree allergens like birch, hazel, hornbeam, oak
and alder allergens, food allergens like peanut, soybean and milk allergens .
The allergen incorporated into the fast dispersing solid dosage form may be
in the form of an extract, a purified allergen, a modified allergen, a
recombinant allergen or a mutant of a recombinant allergen. An allergenic
extract may naturally contain one or more isoforms of the same allergen,
whereas a recombinant allergen typically only represents one isoform of an
allergen. In a preferred embodiment the allergen is in the form of an extract.
In another preferred embodiment the allergen is a recombinant allergen. In a
further preferred embodiment the allergen is a naturally occurring low IgE-
binding mutant or a recombinant low IgE-binding mutant.
Allergens may be present in equi-molar amounts or the rafiio of the allergens
present may vary preferably up to 1:20.
In a further embodiment of the invention the low IgE binding allergen is an
allergen according to WO 99/47680, WO 02/40676 or WO 03/096869 A2.
Dosage f~rm
The dosage form of the invention is preferably produced by lyophilisation.
Preferably pH is adjusted prior to solidification of the allergen and matrix
containing solution to avoid denaturation of the allergen, precipitation and
assure a stable product. The optimum pH for different allergens in solution
span almost the entire pH range as does their isoelectric point (p1). Mixtures
of allergens like extracts equally have optimum for solubility and stability
determined by factors like the concentration of the individual allergens in
the
extract. Therefore an individual determination of a feasible range of pH for a
formulation according to this invention may be envisaged. The optimum pH
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for the allergen in question is determined by carrying out accelerated
stability
studies with formulations with different pH. The design of such studies is
known to the person skilled in the art of formulating allergen vaccines.
Preferably, dosing solutions containing an allergen extract should be
adjusted to pH between 3.5-10, more preferably 4-9, most preferably 6-9.
Furthermore, it is well known in the art that ionic strength may be a
parameter affecting the stability of a freeze-dried solid dosage form
primarily
through its effect of the freeze-drying processes. Also it is known to affect
precipitation at high ionic strengths. Accordingly an optimum must be
established by measurements well known to the person skilled in the art.
Preferably the ionic strength of an extract of 10 p.g/ml is in between 1-1500
p,S/cm, more preferably between 300 - 800 ~.S/cm, most preferably about
500 p.S/cm, for a matrix and allergen containing system it is preferred that
the
ionic strength is between 1-2000 p.S/cm, more preferably 500-1500 p.S/cm.
Classical incremental dosage desensitisation, where the dose of allergen in
the form of a fast dispersing solid dosage form is increased to a certain
maximum relieves the symptoms of allergy. The preferred potency of a unit
dose of the dosage form is from 150 - 1000000 SCE-u/dosage form, more
preferred the potency is from 500 - 500000 SQ-u/dosage form and more
preferably the potency is from 1000 - 250000 SQ-u/dosage form, even more
preferred 1500-125000 SQ-u/dosage form most preferable 1500-75000 SQ-
u/dosage form.
In another embodiment of the invention the dosage form is a repeated mono-
dose, preferably within the range of 1500-75000 SQ-u/dosage form.
In further embodiment of the invention the allergen dosage form dissolved in
saliva is not swallowed until 3 min after administration in order to allow
sufficient contact time for e.g. absorption over the mucosal membrane in the
mouth.
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In yet a further preferred embodiment the allergen dosage form is not diluted
in the oral cavity e.g. by intake of a fluid like water until after 5 min.
5 The fast dispersing solid dosage form according to the invention may be
manufactured and packaged in disposable single dose blister packs as
described in US 5,729,958 and US 5,343,762. Examples of suitable blister
packs are All Aluminium Blister packs, blister packs made of polymers e.g.
polypropylene, blister packs of PVC and blister packs formed from
10 PVC/PVdC laminate and sealed with e.g. aluminium laminated to calendered
kraft paper, Aclar~ or Triplex.
In one embodiment of the invention, the fast dispersing dosage form is
manufactured and packed in blister packs formed from PVC/PVdC laminate
15 and sealed with aluminium laminated to calendered kraft paper. In another
embodiment hereof the blister pack are enclosed in an aluminium sachet of
suitable size, composed of aluminium laminated to calendered kraft paper.
In yet another embodiment the fast dispersing dosage form is packed in
20 blister packs formed from aluminium and sealed with aluminium laminated to
calendered Icraft paper.
In a further embodiment the fast dispersing dosage form is packed in
multilamilar blister packs formed from e.g. five layer aluminium laminate and
25 sealed with aluminium laminated to calendered kraft paper.
In yet another embodiment the fast dispersing dosage form is packed in
blister packs formed from aluminium laminate and sealed with aluminium
laminated to calendered kraft paper in such a way that is difficult for
children
30 to open the blister pack e.g. child resistant packs
A non-compressed fast dispersing solid dosage form is normally
characterized by a low mechanical strength compared to compressed tablets,
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because of the inherent nature of such a non-compressed dosage form. This
may result in the release of residual particles containing the allergen on
removal from the blister pocket and during handling of the dosage form by
the patient. In most situations this is of no or mainly cosmetic importance.
However, this is especially detrimental when the active ingredient is an
allergen, because low amounts allergen can elicit an allergic reaction in a
disposed person or sensitise. Normally exposure is in the range of 10
~.g/year to major allergen protein accumulated for e.g. pollen allergens or
dust mite'allergens, which are adequate to give sensitisation or symptoms.
Upon handling the solid dosage forms, allergens may come in contact with
target organs like the airways or the eye and elicit a response in an allergic
person. One dosage form may contain as much allergen as a person is
exposed to in the course of one year or more depending upon the nature of
the exposure. It is possible to induce eye symptoms in allergic patients using
a conjunctiva) allergen challenge. Sased on such challenge studies ii can be
estimated how much allergen extract is needed to induce conjunctiva)
symptoms. In a population of patienfis with severe grass-pollen induced
hayfever, the lowest dose of grass pollen extract causing conjunctiva)
symptoms was proposed to be 3000 SC,a-U/ml x 0,05 ml = 150 SQ-U (median
value) (S. R. ~urham, S. M. Walker, E. M. ~arga, M. R. Jacobson, F.
O'Srien, W. Noble, S. J. Till, Q. A. Hamid, and K. T. Nouri-Aria. Long-term
clinical efficacy of grass-pollen immunotherapy. N.EngLJ.Med. 341 (7):468-
475, 1999).
Thus, in one embodiment of the dosage form of the invention less than 500
SQ-U is released from each solid dosage form during manual handling, more
preferably less than 250 SQ-U, most preferably less than 150 SQ-U,
In order to ensure that allergen containing residues from the solid dosage
form is not released to the environment upon opening the blister pack, it is
important that the friability of the dosage form is as low as possible without
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jeopardising the allergen release from the dosage form following oral
administration.
In a preferred embodiment of the present invention the residual content of
dust in the blister pack after removing the dosage form do not exceed 2 % of
total allergen content, more preferred 0.5 % of total allergen content of a
solid
dosage form and more preferably 0.2 % of total allergen content of a solid
dosage form and most preferably 0.1 % of total allergen content of a solid
dosage form.
Normally friability testing of compressed tablets is preformed as set out in
the
Pharmacopeia E.P. 2.9.7 and USP <1216>, wherein loss of weight is
assessed as a parameter of an intact dosage form. Accordingly, the
intactness of the current dosage form may be assessed by visual inspection
and measurement of tablet weight upon having been subject to such a
mefihod. Alternatively, due to the low weight of dosage forms according to
fibs
invention the weighing can be replaced with an immune assay specific for the
allergen in question.
The use of a modified friability test has been found to be a useful tool in
assessing which compositions are most stable with respect to robustness
and mechanical strength. In an embodiment fibs friability of said solid dosage
form measured as the amount of allergen released is less than 500 SQ-U per
solid dosage form, more preferably less than 250 SQ-U per solid dosage
form, most preferably less than 150 SQ-U per solid dosage form in any
suitable friability test that exerts a sufficient external force on the
compositions to be tested. In a more preferred embodiment the friability
measured as the amount of allergen released is less than 500 SQ-U per solid
dosage form, more preferably less than 250 SQ-U per solid dosage form,
most preferably less than 150 SQ-U per solid dosage form in a friability test
performed according to the Pharmacopeia. In an even more preferred
embodiment the friability measured as the amount of allergen released is
less than 500 SQ-U per solid dosage form, more preferably less than 250
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SQ-U per solid dosage form, most preferably less than 150 SQ-U per solid
dosage form in an assay comprising the following steps;
a) placing individual units of solid dosage form contained in sealed blister
pack unit in an equipment suitable for friability measurements
b) moving it for an appropriate time and at an appropriate velocity
c) removing the sealed solid dosage form unit
d) opening the sealed solid dosage form unit and emptying the unit content in
a container/ placing the fast dispersing dosage form unit and any residues in
a container
e) removing the solid dosage form unit from the container leaving any loose
residuals in said container
f) performing an allergen specific assay on said residues determining the
allergen content in said residues
g) optionally calculating the percentage allergen content in said residues of
the total allergen content of the solid dosage form unit.
In a preferred embodiment of the friability method the units are rotated 100
turns at 25 ~1 rpm and the allergen content is determined by an ELISA
assay.
Furthermore, the oral dosage form preferably has an appealing appearance.
Hence, as a part of the quality control the fast dispersing solid dosage forms
according to the invention are preferably subjected to visual inspection, e.g
for parameters such as colour, shape, irregularities and defects.
In order to ensure optimum compliance of the patient, it is preferred that the
patients perceive the dosage form as being pleasant when it is placed in the
mouth and allowed to disintegrate. Thus, the dosage form is preferably also
tested for mouth feel.
As allergens are very bio-potent for the allergic person i.e. even small
amount may trigger a response, it is preferred that the content of allergen is
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uniform during treatment e.g. to ensure that a response pattern experienced
for a patient may be reproduced when the same dose is administered.
Preferably the variation of content of allergen of units within a blister pack
is
within ~10°l°, preferably within ~7%, most preferable within ~5
°l° compared to
the dose set.
A blister pack may contain any conceivable number of fast dispersing solid
dosage forms. In preferred embodiment the blister pack contains 1-100 solid
dosage forms and more preferably 5-35 solid dosage forms. The blister
packs may further be packed in appropriate containers in accordance with
any particular dose regime that is required to desensitise a patient.
Furhermore, the present invention relates to a method of producing a fast
dispersing non-compressed solid dosage form according to claim 1,
comprising the steps of:
preparing an aqueous dosing solution of the pharmaceutically active
substance and maltodextrin and optionally one or more further matrix forming
agents and suitable excipients,
introducing the solution into depressions of a multilayer laminated blister
sheet,
subjecting the loaded sheet to freeing and freeze-drying using standard
conditions of shelf temperature and chamber pressure.
Moreover, the present invention relates to a method of obtaining a fast
dispersing non-compressed allergen vaccine solid dosage form suitable for
oromucosal administration comprising
1 ) producing a fast dispersing, non-compressed solid allergen vaccine
dosage form
2) measuring the friability of said dosage form in an assay comprising the
steps of
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a) placing a solid dosage form contained in a sealed blister pack unit in an
equipment suitable for friability measurements
b) moving it for an appropriate time and at an appropriate velocity
c) removing the sealed solid dosage form unit
5 d) opening the sealed solid dosage form unit and emptying the unit in a
container/ placing the fast dispersing dosage form unit in a container
e) removing the solid dosage form unit from the container leaving any loose
residues in said container
f) performing an immunochemical allergen specific assay on said residues
10 detecting the amount of allergen content in said residues
g) calculating the percentage of allergen content in said residues in
comparison to total allergen content of the solid dosage form unit
h) detecting whether the dosage form fulfills the requirements for low
friability.
3) repeating 1 ) and 2) until the requirements for the dosage form is
fulfilled.
Treatment
The fast dispersing solid dosage form according to the invention can be
prepared by a sublimation process according to the process disclosed in U.S.
patent No. 4, 371,516. Accordingly, a solidified solution of the allergen and
the matrix forming excipients is subjected to sublimation. The sublimation
process is preferably carried out by freeze-drying the solution. The solution
is
contained in a depression of the blister pack during the freeze-drying step to
produce a solid form in any desired shape. The blister pack can be cooled
using liquid nitrogen or solid carbon dioxide. After the freezing step the
frozen
solution in the blister pack is subjected to reduced pressure and, if desired,
controlled application of heat to aid the sublimation of the solvent.
Clinical allergy manifestation and symptoms are several and may vary
depending on the sensitized individual and the allergy inflicted. Common are
symptoms like edema, itching, redness and running of the eyes and nose
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(rhinitisconjunctivitis) and symptoms from upper and lower airway like
wheezing, coughing, shortness of breath, skin condition like eczema, urticaria
and itching. Other symptoms like fatigue are also experienced. Symptomatic
treatment aims at reducing or affecting severity of the symptoms or reducing
the need for other drugs given in parallel. Symptomatic drugs include
antihistamines like H1 and H2 receptor antagonists, intranasal and systemic
corticosteroids, non-steroid anti-inflammatory drugs, nasal decongrdtans like
adrenoceptor agonists. Treatment and relief of one or more allergic
symptoms or the reduction of the need for other medication is a further object
of this invention.
Thus, the present invention relates to a method of preventing or treating a
disease comprising oromucosal administration of an effective amount of a
dosage form according to the invention.
More specifically, the present invention relates to a mefihod for preventing
or
treating allergy or alleviating symptoms of allergy comprising oromucosal
administration of an effective amount of an allergen vaccine dosage form
according to the invention.
The present invention also relates to a pharmaceutically active substance for
the manufacture of a fast dispersing non-compressed solid dosage form
according to the invention.
More specifically, the present invention relates to an allergen for the
manufacture of a fast dispersing non-compressed allergen vaccine solid
dosage form according to the invention.
Further, the present invention relates to a fast dispersing non-compressed
solid dosage form according to the invention for oromucosal prevention or
treatment of a disease.
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More specifically, the present invention relates to a fast dispersing non-
compressed allergen vaccine solid dosage form according to the invention for
oromucosal prevention or treatment of allergy or alleviation of allergic
symptoms.
Also, the present invention relates to the use of a pharmaceutically active
substance for the manufacture of a fast dispersing or non-compressed solid
dosage form according to claim 1 for oromucosal prevention or treatment of a
disease.
More specifically, the present invention relates to the use of an allergen for
the manufacture of a fast dispersing or non-compressed allergen vaccine
solid dosage form according to claim 1 for oromucosal prevention or
treatment of allergy or alleviation of allergic symptoms.
Sublingual immunotherapy can be regarded as a way of inducing tolerance
inducing mucosal vaccination. The mucosa of the mouth is rich in dendritic
cells with a strong potential for antigen presentation. The dendritic cells
are
believed to process the allergens and then migrate to the local lymph nodes
where they present allergen derived peptides to allergen specific T cells.
During sublingual immunotherapy this dendritic cell - T cell interaction is
believed to induce T cells with regulatory potential or to increase the ratio
of
allergen specific Th1 cells to allergen specific Th2 cells. A number of
immunological parameters monitored during the allergy vaccination may be
suitable markers for effects or efficacy of the treatment, alone or in
combination respectively. These include systemic and mucosal antibody
responses e.g. specific IgA, IgG and IgE antibodies; cytokine levels e.g.
INFgamma, IL-2, IL-4, IL-5, IL-10, IL-12 and TNF alpha in blood or mucosal
secretions; activation, chemotaxis, proliferation, signalling, cytokine
production and other responses of regulatory T-cells, Th1 cells, TH2 cells,
CD8 cells, other T cell subsets or B-cells or NK cells, and cell surface
marker
expression such as CD (cluster of differentiation) markers e.g. CD4, CDB,
CD23, CD25, CD62L, CLA, beta7, CCR9, CD69, CD45R0, CCR3, CXCRS,
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effector cell function such as total histamine content of basophils;
eosinophil,
basophil, lymphocyte, monocyte numbers in blood, tissue and secretions;
eosinophil, basophil, lymphocyte, monocyte mediator release, cytokine
production, activation, chemotaxis, proliferation, signalling and other
responses.
In a preferred embodiment the dosage form according to the present
invention has a profile where one or more of the following immunological
changes can be found; an increased allergen specific IgG response, an
increased allergen specific 1gA response, reduced allergen specific IgE
response, few local side effects; reduced allergen specific effector responses
of eosinophils, basophils, lymphocytes and/or monocytes; induction of T cells
with regulatory potential, increased ratio of allergen specific Th1 cells to
allergen specific Th2 cells, induction of other cells with regulatory
potential,
reduced allergen specific Th2 response.
Allergy is also a known disease in animals especially domestic and
companionship animals. It is known in the art that they develop allergies
toward numerous allergen sources including grass, house dust mites, and
parasites. Hematopgagus, i.e. bloodsucking insect infestation is known to
lead to a hypersensitive response called flea allergic dermatitis (FAD). In a
preferred embodiment of the current invention allergens for animal vaccines
include allergens originating or transferred from parasites like ectoparasites
(e.g. fleas, ticks, mosqistos, flies), parasitic helminth venom (like hearth
worm
e.g. Dirotilaria or onchocerciasis e.g. Onchocerca) and house dust mite.
More preferred are saliva allergens from fleas like Ctenocephalides e.g. C.
canis and C. fells, hard ticks likes Ixodes, Arnblyomma, soft ticks like
Ornithodoros and from midges like Culicoides.
Dosage forms containing microcapsules
Peyer's patches are aggregates of lymphoid nodules located in the wall of
the small intestine, large intestine and appendix and are an important part of
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body's defense against the adherence and penetration of infection agents
and other substances foreign to the body. Peyer's patches are also known as
folliculi lymphatic aggregate. Similar folliculi lymphatic aggregate can be
found
in the respiratory tract, the rectum, the nasal cavity, the oral cavity, the
pharynx, the genitourinary tract, large intestine and other mucosal tissues of
the body. The said tissues may in general be referred to as mucosally-
associated lymphoid tissues (MALT).
It has been shown that pharmaceutically active substances formulated as
microcapsules having a proper size and suitable physico-chemical properties
may be effectively taken up by Peyer's patches and MALT.
Accordingly, an additional aspect of the present invention relates to a dosage
form, wherein at least a part of the active substance is present in the form
of
microcapsules embedded in the matrix, the microcapsules comprising a first
encapsulating agenfi and the active substance. 1li/ithout being bound by
theory it is believed that for a number of active substances, in particular
allergens, it is possible to obtain the intended therapeutic effect by
microcapsules, which may be taken up by the MALT or allowed to elicit its
effects via the MALT. In a preferred embodiment of the invention, the active
substance is present in the matrix both in form of microcapsules and in the
form of molecules in direct contact with the matrix. It is believed that in
this
embodiment the active substance is taken up and/or allowed to elicit its
effects by two different mechanisms, i.e. both via the MALT and via
immunosystem stimulation elicited by free allergens, and hence an enhanced
therapeutic effect is obtained as compared to the situation, where the active
substance is formulated either as microcapsules or in direct combination with
the matrix.
In addition to enhanced therapeutic effects, the use of microcapsules
involves the advantage of protecting the pharmaceutical active substance
from degradation, both during production and storage of the dosage forms,
and in the process of administration of the active substance to the patient.
As
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described in more detail elsewhere in this application, this is particularly
important, when the active substance is an allergen. The use of
microencapsulation to protect sensitive bioactive substances from
degradation has become well-known. Typically, a bioactive substance is
5 encapsulated within any of a number of protective wall materials, usually
polymeric in nature. The agent to be encapsulated can be coated with a
single wall of polymeric material (microcapsules), or can be homogeneously
dispersed within a polymeric matrix (microspheres). (Hereafter, the term
microcapsules refers to both microcapsules and microspheres and the terms
10 "encapsulation" and "microencapsulation" should be construed accordingly).
The amount of substance inside the microcapsule can be varied as desired,
ranging from either a small amount to as high as 95% or more of the
microcapsule composition. The diameter of the microcapsule is preferably
less than 20 pm, more preferably less than 15 pm, more preferably less than
15 10 pm and most preferably between 1 and 10 pm.
Furthermore, the use of microcapsules involves the advantage of preventing
the release of the active substance from the dosage form. As described in
more detail elsewhere in this application, this is particularly important,
when
20 the active substance is an allergen.
The encapsulating agent may be any biodegradable agent, preferably a
polymeric agent. Preferably, the first encapsulating agent is selected from
the
group consisting of poly-lactide, poly-lactid-polyethylene glycol), poly(DL-
25 lactide-co-glycolide), poly(glycolide), copolyoxalates, polycaprolactone,
poly(lactide-co-caprolactone), poly(esteramides , polyorthoesters and poly(3-
hydroxybutyric acid), and polyanhydrides, most preferably poly(DL-lactide-co-
glycolide). Other examples of encapsulating agents are poly(butyl-2-
cyanoacrylate), poly(3-hydroxybutyrate) and polyanhydride copolymers of
30 fumaric and sebacic acid, poly(FA:SA). Also, suitable encapsulating agents
for use according to the present invention include those derived from animal
or vegetable proteins, such as gelatines, dextrins and soy, wheat and
psyllium seed proteins; gums such as acacia, guar, agar and xanthan;
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polysaccarides; starch and modified starch, alignates;
carboxymethylcellulose; carrageenans; dextrans; pectins; synthetic polymers
such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide
complexes such as gelatine-acacia complexes. In one embodiment of the
. 5 invention two or more encapsulating agents are used. Preferably, the
encapsulating agent is selected so as to make the microparticles
hydrophobic. It is believed that hydrophobic microparticles are more easily
taken up by the MALT or allowed to elicit its effects via the MALT.
In one preferred embodiment of the invention, the microcapsule-containing
dosage form is formulated as a tablet, i.e. a coherent dosage form unit. In
another preferred embodiment, the microparticle-containing dosage form is
formulated as a granular composition, e.g. a granular composition suitable for
preparing a compressed tablet. Also, the dosage form of the invention,
wherein the pharmaceutically active substance is present in direct
combination with the matrix forming agent, may be formulated as a granular
composition, e.g. a granular composition suitable for preparing a compressed
tablet.
The present invention further relates to a compressed tablet comprising the
granular composition of the invention.
Furthermore, the present invention relates to an aqueous dosing solution for
preparing a fast-dispersing solid composition suitable for oromucosal
administration of a pharmaceutically active substance, the dosing solution
comprising
(a) a first matrix forming agent in the form of maltodextrin having a dextrose
equivalent (DE) of between 1 and 20, and
(b) microcapsules comprising a first encapsulating matrix forming agent and
the active substance.
Finally, the present invention relates to a method of preparing the dosage
form according to the invention comprising the steps of:
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preparing microcapsules comprising a first encapsulating matrix forming
agent and a pharmaceutically active substance,
preparing an aqueous dosing solution of the microcapsules and maltodextrin
and optionally one or more further matrix forming agents and suitable
excipients,
spray-freezing the dosing solution to produce primary granules, and
freeze-drying the primary granules to produce secondary granules.
Definitions
The term "maltodextrin" means a partly hydrolysed starch having a dextrose
equivalent (DE) of between 1 and 20.
The term "fast dispersing dosage form" refers to dosage forms which
disintegrate in less than about 90 seconds, preferably in less than 60
seconds, preferably in less than 30 seconds, more preferably in less than 20,
even more preferably in less than 10 seconds in the oral cavity, even more
preferred in less than 5, most preferably in less than about 2 seconds of
being placed in the oral cavity.
The term "stable" refers to dosage forms where the loss in allergen content of
at least one major allergen according to the method described in Example 1
is less than 50 % of the initial content.
The term "low friability" refers to the amount of residual material that is
lost
from the dosage form when it is subjected to an external force. The solid
dosage form has a sufficient friability and robustness to be transported,
stored and handled if the residual material lost contains less than 500 SQ-
units per solid dosage form, more preferably less than 250 SQ-units per solid
dosage form, most preferably less than 150 SQ-U per solid dosage form of
the total allergenic content of the dose. For the purpose of the present
invention, the friability may be measured by a method according to the
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present invention or may be measured by a modified method according to
the European Pharmacopeia.
The term "non-compressed" refers to a solid dosage form, which is
manufactured by removal of a liquid from a solidified sysfiem comprising
matrix forming agents, active ingredient and other suitable ingredients
resulting in a an allergen comprised solid matrix.
The term "solid dosage form" refers to a dosage form, which is not a liquid,
nor a powder, e.g. a tablet or a granular composition, when it is administered
in the oral cavity.
"Tensile strength 6 " is calculated according to the following equation
6 = 3Wa x 9.8 Nmm-2/ 2d2b
where w = Peak load to fracture (kgF)
a= distance between supports
d = thickness of the fast dispersing solid dosage form (mm)
b = diameter of the fast dispersing solid dosage form (mm)
"Peak load to fracture" means the peak force required to fracture a unit in a
three point bend test using an appropriate instrument (e.g. CTS, Engineering
Systems, 1 Loach Court, Radford Bridge Road, Nottingham NG8 1 NA).
The term "oromucosal" refers to a dosage form that is placed under the
tongue or anywhere else in the oral cavity that allows the active ingredient
to
come in contact with the mucosa of the oral cavity or the pharynx of the
patient.
The term "mono-saccharide" refers to any organic molecule containing six
carbons, whether in the form of a ring or a linear molecule. The term "di-
saccharide" refers to any saccharide comprising any combination of two
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mono-saccharides. The term "tri-saccharide" refers to any saccharide
comprising any combination of three mono-saccharides.
The "dosing solution" means the non-solid mixture of the solvent, the matrix
forming agents, the active substance, and other optional excipients subjected
to solidification.
The term "allergen" refers to any naturally occurring protein or mixtures of
proteins that have been reported to induce allergic, i.e. IgE mediated
reactions upon their repeated exposure to an individual. Examples of
naturally occurring allergens include pollen allergens (tree-, weed and herb-
and grass pollen allergens), mite allergens (from e.g. house dust mites and
storage mites), insect allergens (inhalant, saliva- and venom origin
allergens), animal allergens from e.g. saliva, hair and dandruff from e.g.
dog,
cat, horse, rat, mouse, etc., fungis allergens and food allergens. The
allergen
may be used in the form of an allergen extract, a purified allergen, a
modified
allergen or a recombinant allergen or a recombinant mutant allergen, any
allergen fragment above 30 amino acids or any combination thereof.
SQ-unit: The SQ-unit is determined in accordance with ALK-Abello
A/S°s "SQ
biopotency"-standardisation method, where 100.000 SCE units equal the
standard subcutaneous maintenance dose. Normally 1 mg extracts contains
between 100000 and 1000000 SQ-unit depending on the allergen source
from which they originate and the manufacturing process used. The precise
allergen amount can be determined by means of immunoassay i.e. total
major allergen content and total allergen activity. In this field of
expertise,
there is no international accepted standardisation method. Hence, if extracts
of other origins are used, they need to be standardised against an ALK-
Abello A/S extract, which is a well-known procedure for the person skilled in
the art. The subject matter is dealt with in "Allergenic extracts", H. Ipsen
et al,
chapter 20 in Allergy, principle and practise (Ed. S. Manning) 1993, Mosby-
Year Book, St. Louis and Lrowenstein H. (1980) Arb Paul Ehrlich Inst 75:122.
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"Uniformity of content" shall mean the variation of the doses unit from the
stated dose.
"Water content" shall mean the content of residual water in a solid dosage
5 unit determined quantitatively using a Karl Fischer titration principle.
This
method is based on the principle that a given amount of 12 leads to a
transformation of an equivalent amount of water (European Pharmacopoiea
2.5.12)
10 As used herein "Water activity aw" is the effective water in a sample.
Water
activity measurements are carried out using methods known to the person
skilled in the art, for example chilled mirror dew point technology, relative
humidity with sensors that change electrical resistance or capacitance or
using a lithium chloride electrode:
aw can be calculated according to the following equation
aw = pips =ERH (%)l100
where
p = partial pressure of water vapor at the surface of the product
ps = saturation pressure, or the partial pressure of water vapor above pure
water at the product temperature.
ERH = equilibrium relative humidity.
EXAMPLES
Abbreviations:
API: Active Protein Ingredient
ELISA: Enzyme Linked Immuno Sorbent Assay
DDT: Dithiothreitol
HRP: Horse Radish Peroxidase
LIA: Magic Lite specific IgE assay
LITE-reagent: Luminescence labbelled anti-gE
PMP: Para Magnetic Particles
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SDS-PAGE: Sodium dodecyl sulphate poly-acryl amide gel electrophoresis
TMB:Tertametylbenzidine.
EXAMPLE 1
Grass extract
Grass pollen extract was prepared according to the method describes in
Ipsen and Lowensten (1983) Jour. Allergy. Clin. Immunol. 72:2, page 150-
159. In short grass pollen was extracted in ammonium hydrogen carbonate,
for 20 hours at 5° C. Particulate matter was removed by centrifugation
and
the supernatant was dialysed against water (3 times), lyophilised and stored
cold until reconstitution.
Solid dosage:
Manufacturing process:
1. MQ water is added to a beaker with a magnet stirrer.
2. Mannitol and sorbitol, if any, is added and dissolved under stirring.
3. Maltodextrin and PEG, if any, is added and dissolved under stirring.
4. Allergen extract, if any, is added.
5. If allergen is present, pH is adjusted to pH = 7-8 using hydrochloric acid
(2N) or sodium hydroxide (2N).
6. 250 p1 of the solution was dosed into pre-formed blister packs. The
solutions were dosed under ambient temperature conditions.
7. After dosing, the filled blister packs were freezed at - 80 °C. The
units
were freeze-dried using standard conditions of shelf temperature and
chamber pressure.
Short descriptions of analytical methods:
Visual inspection: All units were subjected to visual inspection e.g colour,
shape, irregularities and defects to ensure acceptable appearance.
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Disintegration: The test was performed as described in the current European
Pharmacopoeia or the current USP.
Water content: The residual water was determined using a Karl Fischer
titration principle. The method gives a quantitative determination of the
water
content in a sample based on the principle that a given amount ofi 12 leads to
transfiormation ofi an equivalent amount of H20.
Composition
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10
Code MannitolMaltodextrinSorbitol Allergen extract
A 3 w/w-%5 w/w-% - 0,002 w/w-
B 3 w/w-%5 w/w-% 0,1 w/w-%0,002 wlw-
C 3 w/w-%5 w/w-% 1 w/w-% 0,002 w/w-
* The amount of API dependent on the reconstitution factor of the specific
batch API.
Results
of
analytical
tests
Code Water Disinte- Visual inspection
content gration
A 4.5% 1 sec. Very difficult to remove solid
unit in one
piece from blister pack
B 4.4/~ 1 sec. Very difficult t~ remove solid
unit in one
piece from blisfier pack
B 3.8% 1 sec. Very difficult to remove solid
unit in one
piece from blister pack
It has been shown possible to produce freeze-dried solid dosage forms with
various contents of mannifiol, maltodextrin, allergen extract with and without
sorbitol. The dosage forms all had a disintegration time of 1 sec.
EXAMPLE 2
Code MannitolMaltodextrinSorbitol
A 3 w/w-% 5 w/w-% -
B 3 w/w-% 5 w/w-% 0,1 w/w-
C 3 w/w-% 5 w/w-% 1 w/w-
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10
Results
of analytical
tests
Code Water DisintegrationVisual inspection
content
A 4.6% n.m. Impossible to remove solid
unit in
one piece from blister pack
B 4.6% n.m. impossible to remove solid
unit in
one piece from blister pack
C n.m. n.m. Impossible to remove solid
unit
from blister pack
* It was only possible to remove 3 solid units from the blister pack, which is
why the test for disintegrations is based on only 3 units.
It has been shown possible to produce freeze-dried solid dosage forms with
various contents of mannitol, maltodextrin and/or sorbitol.
EXAMPLE 3
Code MannitolMaltodextrinSorbitol PEG 6000
A 5 w/w-/~10 w/w-/~ 0.1 wlw-%-
B 10 w/w-%20 w/w-% 0,1 w/w-%-
C 10 wlw-%20 w/w-% - _
D 5 w/w-% - 0.1 w/w-%5 w/w-
E 10 w/w-%- 0.1 w/w-%10 w/w-
F 10 w/w-%- - 10 w/w-
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Results
of
analytical
tests
Code Water DisintegrationVisual inspection
content
A n.m. n.m. Impossible to remove solid unit
in one
piece from blister pack
B 5.1 % 3 sec. Very difficult to remove solid
unit in one
piece from blister pack
C n.m. n.m. Very difficult to remove solid
unit in
one piece from blister pack
D n.m. n.m. Impossible to remove solid unit
in one
piece from blister pack
E n.m. n.m. Impossible to remove solid unit
in one
piece from blister pack
F n.m. n.m. Impossible to remove solid unit
in one
piece from blister pack
It has been shown possible to produce freeze-dried solid dosage forms with
various contents of mannitol andlor maltodextrin and/or sorbitol and/or PEG.
5 A dosage form comprising mannitol, maltodextrin and sorbitol had a
disintegration time of 3 sec.
EXAMPLE 4
Code MannitolMaltodextrinSorbitol PEG 6000
A 5 w/w-% 20 w/w-% 0.1 w/w-% -
B 5 w/w-% 20 w/w-% 0.1 w/w-% 3 w/w-
C 5 w/w-% 35 w/w-% 0.1 w/w-% -
D 5 w/w-% 35 w/w-% 0.1 w/w-% 3 w/w-
E 5 w/w-% 35 w/w-% 0.2 w/w-% -
F 5 w/w-% 35 w/w-% 0.2 w/w-% 3 w/w-
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Results
of
analytical
tests
Code Water DisintegrationAppearance
content
A n.m. 5 sec. Possible to remove solid unit
in one
piece from blister pack
B n.m. 2 sec. Impossible to remove solid unit
in one
piece from blister pack
C n.m. 81 sec. Possible to remove solid unit
in one
piece from blister pack
D n.m. 58 sec. Possible to remove solid unit
in one
piece from blister pack
E n.m. 95 sec. Very difficult to remove solid
unit in one
piece from blister pack
F n.m. 83 sec. Very difFicult to remove solid
unit in one
piece from blister pack
It has been shown possible to produce freeze-dried solid dosage forms with
various contents of mannitol and/or maltodextrin and/or sorbitol and/or PEG.
A dosage form comprising mannitol, maltodextrin and sorbitol had a
disintegration time of 3 sec.
EXAMPLE 5
This example relates to the preparation of a granular composition of granules
having a matrix composed of maltodextrin, mannitol and sorbitol, wherein the
matrix comprises microencapsulated allergen (MEA), and to the preparation
of compressed tablets from the granular composition.
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Materials
Encapulating agent: Poly-D,L-Lactide-Glycolide (DL-PLG) (60/40) with an
MW of 40,000 g/mol, obtained from Birmingham Polymers in the USA.
Active substance: Phl p extract in MEA-particles.
Mannitol: Ph. Eur. <559>, No. 281048 from Unikem.
Sorbitol: Ph. Eur. <435>, No. 340927 from Nomeco.
Maltodextrin: NF 18, type CPUR01915 (18 DE) from Cerestar.
Talcum: Ph. Eur. <438>, No. 297911 from Unikem.
Magnesium sterate: Ph. Eur. <229>, No. 280560 from Unikem.
Test methods for compressed tablets
Resistance to crushing
The tablet is placed horizontally on a support against a first vertical plate.
A
piston fitted with a second vertical plate at its distal end, the two plates
being
disposed parallel, is moved against the tablet, and the pressure in N applied
at the time of crushing of the tablet is measured.
Friability
20 tablets are dusted off and weighed and then placed in a cylinder fitted
with
internal ribs. The cylinder is rotated at 25 rpm for a selected period of
time,
removed from the cylinder, dusted off and weighed. The difference in initial
and final weight is calculated in percent and expresses the friability.
Preparation of MEA
1. Homogenisation.
DL-PLG is dissolved in ethyl acetate (30 w/w %), and the allergen extract is
dissolved in water (13 w/w %). The two solutions are mixed and
homogenised to form an oil/water two-phase emulsion.
2. Emulsifying the oil/water emulsion in an aqueous medium.
The oil/water emulsion is mixed with a 2 w/w % aqueous solution of PVA,
which is saturated with ethyl acetate and buffered to pH =6.8 using sodium
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phosphate and hydrochloric acid, and emulsified to form a water/oil/water
emulsion. The water/oil/water emulsion is passed through an emulsion sieve
in the emulsifying apparatus to form MEA-microcapsules.
3. Extraction of ethyl acetate /PVA.
In order to cure the MEA-microcapsules, ethyl acetate and PVA are
extracted. For the first 10 minutes of the extraction, the temperature is
maintained at 22 °C, after which the temperature is lowered to 12
°C.
4. Up-concentration by means of centrifugation.
The suspension formed in step 3 is subjected to centrifugation.
5. Re-suspension and spray drying.
After centrifugation the microcapsules are re-suspended in water (1800 ml
/25 g) and subjected to spray drying to form the finished microcapsules.
Preparation of granular composition
MEA is suspended in distilled water and mannitol, maltodextrin and sorbitol
are added, and the suspension is stirred. The resulting mixture is sprayed
into a chamber filled with liquid nitrogen, wherein the droplets freeze
immediately. During the spray-freezing, a portion of the droplets will freeze
together, and therefore the frozen particulate composition is optionally
subjected to crushing. The crushed ice particles are sieved and freeze dried
and sieved again to obtain the finished granules.
Preparation of tablets
The tablets were produced using a "Comprex II" tabletting apparatus.
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Composition
Material MEA MannitolMalto-dextrinSorbitolWater
w/w w/w w/w % w/w w/w
% % %
A MEA 100.0
Dosing 6.7 6.7 26.7 6.7 53.3
sol.
Granules 14.3 14.3 57.2 14.3
B MEA 100
Dosing 16.5 8.3 23.3 1.6 50.2
sol.
Granules 33.2 16.7 46.8 3.3
C MEA 100.0
Dosing 16.5 8.3 23.3 1.6 50.2
sol.
Granules 33.2 16.7 46.8 3.3
D MEA 100.0
Dosing 10.9 9.5 11.5 0.0 68.1
sol.
Granules 34.1 29.8 36.1 0.0
E MEA 100.0
Dosing 11.6 9.0 11.3 0.5 67.6
sol.
Granules 35.8 27.8 35.0 1.4
F ME~4 100.0
Dosing 11.3 9.0 11.3 0.7 67.7
sol.
Granules 34.9 27.9 35.1 2.1
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Results
Material 1-5 5-10 <10 STD ResistanceFriability
<
~m ~m % ~m % 10 to crush-
~m ing (N)
%
A M EA 53.8 32.3 91.2 0.1
Dosing sol.
Granules 57.4 30.6 93.0 0.1
Tab l5min. 55.2 29.3 88.7 0.8
Tab 30min. 54,1 29.1 87.2 1.7
B MEA 41,7 33.4 79.0 1.0
Dosing sol.
Granules 57.6 31.4 92.6 0.1
Tab 15min. 57.5 28.8 90.7 0.9
Tab 30min. 58.4 27.5 90.1 1.0
C M EA 41.7 33.4 79.0 1.0
** Dosing sol.
Granules 39.7 34.6 78.1 0.0
Tab 15min.
Tab 30min. 41.0 32.7 77.2 0.5 43.7
D MEA 49.9 40.6 94.4 2.8
Dosing sol.
Granules 44.0 36.8 84.2 0.3
Tab' 30min.53.4 31.1 87.9 0.4 20.1
Tab" 30min.50.6 31.8 85.8 0.5 39.8
E MEA 35.5 30.8 70.6 0.1
** Dosing sol.
Granules 36.9 30.3 71.6 0.5
Tab 15min. 38.1 25.7 66.8 1.5
Granules* 28.7 25.1 57.0 2.5
Tab*. 27.5 22.5 52.2 2.4 76.1
F M EA 35.5 30.8 70.6 0.1
** Dosing sol.
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Granules 36.0 30.6 70.7 0.1
Tab 30 min.32.0 24.1 59.1 1.1 60.8 Positive
Granules* 28.7 25.1 57.0 0.2
Tab* 30 17.4 16.5 35.6 4.0 31.9 Positive
min.
* 0.5 % magnesium stearate and 4.5 % talcum added as lubricants.
** Crushing of granules to reduce size
Tablets compressed at low pressure
" Tablets compressed at high pressure
A number of microcapsule-containing granular compositions and compressed
tablets with different compositions have been prepared. The compressed
tablets all disintegrated quickly, which means that the granular composition
is
easily dispersible. As will appear from the results of the above table, the
particle size distribution of MEA, the granular composition and the tablet
after
dissolution were in all cases closely similar. Thus, it may be concluded that
by use of the present microcapsule-matrix system, it is possible to prepare a
granular composition, which may be used to prepare compressed tablets,
wherein the microcapsules are maintained intact. Also, as will appear from
the results of resistance to crushing and friability, the matrix composed of
mannitol, malfiodextrin and sorbitol is strong, and in any event sufficiently
strong to resist compression into tablets.
25
