Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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I
IMPROVED BIOADHESIVE PHARMACEUTICAL DELIVERY SYSTEM
BACKGROUND OF THE INVENTION
10
1. Field of the Invention
This invention relates to stable solid or semi-
solid water-in-oil emulsions that are usable as
bioadherent, ingestible systems. The systems are
designed to coat and adhere to the oral cavity,
epithelial and mucosal membranes of the esophagus and
gastrointestinal (GI) tract for extended periods of
time. The purpose of the coating is to protect the
mouth tissue and the membranes of the pharynx and the
esophagus, while promoting healing and to enable
release of active drug in a delayed release rate.
Confectionery and chewing gum compositions containing
the emulsions are also described.
2. Description of the Prior Art
Oral pharmaceutical formulations are administered
to patients in many forms, such as liquid solutions,
emulsions, or suspensions, as well as in solid forms
such as capsules or tablets. Preparations
administered in tablet or capsule form are usually
intended to be swallowed whole. It is of significant
advantage to both the patient and clinician that
medication be formulated so that it may be
administered in a minimum number of daily doses from
.- 35 which the drug is uniformly released over a desired
extended period of time. Various techniques have been
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developed for the purpose of including a
pharmaceutical preparation comprising a drug-
containing particle with a coating layer and a
pharmaceutical preparation comprising a continuous
matrix with a drug dispersed therein, such as embedded
into a rigid lattice of resinous material in order to
control the release of drugs. Representative U.S.
Patents covering this technology include the following
patents:
U.S. patent No. 5,059,426 to Cherukuri et al.
discloses a process for preparing a delivery system
comprised of a zinc core material coated with a first
hydrophilic coating comprising a hydrocolloid material
and a second hydrophobic coating selected from the
group consisting of fats, waxes and mixtures thereof.
The delivery system masks the bitter flavor
characteristic of zinc compounds.
U.S. Patent No. 4,597,970 to Sharma et al.
discloses a delivery system capable of effecting a
controlled release of core material comprising: (a)
at least one natural or artificial sweet material and
(b) a hydrophobic matrix consisting essentially of (i)
lecithin; and (ii) an edible material having a melting
point in the range of about 25°C to about 100° selected
from the group consisting of (a) fatty acids having an
iodine value of about 1 to about 10, (b) natural
waxes, (c) synthetic waxes and (d) mixtures thereof;
and (iii) at least one glyceride.
U.S. Patent No. 4,695,467 to Uemura et al.
relates to a sustained release tablet which comprises
easily disintegratable granules containing (a) a drug,
(b) a disintegrating agent selected from the group .
consisting of starch derivatives, gums, cellulose
derivatives and ion-exchange resins, and (c) a water-
soluble polymer selected from the group consisting of
cellulose derivatives, synthetic water soluble
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polymers and polysaccharides, the surfaces of which
granules are treated with a wax selected from the
group consisting of plant or animal wax, hydrogenated
oils and paraffin.
Other forms for delivering pharmaceutical agents
include emulsions and suspensions. Although a need
for water-in-oil emulsions having a high water or
aqueous phase content has long existed for use in
pharmaceutical preparations, such as night creams or
barrier creams and lotions, it has been difficult to
provide such emulsion where the aqueous phase exceeds
45% to 55% on a weight by weight basis. Although many
benefits are to be derived from providing a high water
content in a water-in-oil emulsion system for cosmetic
applications in particular, formulators have not
heretofore been able to add more than about 50% water
to the emulsion without seriously affecting the shelf
life stability of the preparation. It is to be
appreciated in this respect that because of the time
delay that occurs between formulation of a product and
commercial sale, it is undesirable to employ an
emulsion which will break in a short period of time,
particularly when exposed to temperature extremes that
are encountered during transportation and warehouse
storage. Although stability under normal climatic
conditions is an asset, at the very minimum the
emulsion system should be able to withstand
temperatures on the order of 43°C (110°F) for at least
six months without breaking.
water-in-oil- emulsions are used -in barrier
preparations or pore-occluding products to provide a
thin oleaginous layer over the areas of the user's
skin to which the composition is applied. Increasing
the amount of hydrophilic inner phase in the emulsion
decreases the oily feel of the material without
deleteriously effecting the overall utility of the
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formulation. Such formulations have greater customer
appeal because the higher hydrophilic content enhances
the evaporative and thereby cooling effect of the
cream or lotion upon application. Products formulated
from these emulsion systems are described in U.S.
Patent 4,385,049 to Robert C. Cuca.
. The use of water-in-oil emulsions as a liquid or
semi-liquid system for oral use have not been
successful. U.S. Patent No. 2,948,686 to Gianladis
describes water-in-oil emulsions but the patentee was
not able to incorporate more than about 52% water in
the emulsion system.
The present invention overcomes these
deficiencies by preparing an orally useable and stable
solid or semi-solid emulsion or suspension having an
internal hydrophilic phase with a multifunctional
hydrophobic external phase containing at least three
separate components, an emulsifier, a glyceride ester
and a wax material. Such systems enable the inventive
formulation, when taken orally to coat and protect the
oral cavity, and membranes of the esophagus and
pharynx while enabling an active drug to be released
from the formulation in a delayed rate of release.
SUI~iARY OF THE INVENTION
This invention relates to the preparation of a
solid or semi-solid bioadherent, orally ingestible
system, which comprise: a water-in-oil emulsion system
having at least two phases, one phase comprises from
about 25% to about 75o by volume of an internal
hydrophilic phase and the other phase comprises from
about 25% to about 75% by volume of an external
hydrophobic phase, wherein the external hydrophobic ,
phase is composed of three components, a) one
component being about 5% to about 50% of an ,
emulsifier, b) a second component being about Oo to
about 75% of a mixture of glyceride esters of long
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chain fatty acids, and c) a third component being 10~
to about 50~ of a wax material. The wax material
preferably has a melting point within the range of
about 50°C to about 200°C.
1 5 In a preferred embodiment the hydrophilic phase
contains an active pharmaceutical material which is
water-soluble.
In another preferred embodiment, water-insoluble
active pharmaceutical materials are used in the
hydrophobic phase.
Additional preferred embodiments involve
selecting the hydrophilic phase from water, glycerine,
sorbitol solutions, sugar syrups, polymer solutions
and mixtures thereof. In contrast, the hydrophobic
phase contains glyceride esters selected from the
group consisting of long chain fatty acids having from
12 to 32 carbon atoms.
The emulsion of the invention also contain
emulsifiers. Preferably, the emulsifiers are soluble
in the hydrophobic (lipoidal) or external phase.
Suitable emulsifiers are those oil miscible surface
active compounds which are acceptable for use in
foods, pharmaceuticals, and/or cosmetics. Examples of
such emulsifiers are low molecular weight
polyglycerols which have been esterified with fatty
acids or fatty acid esters, or mono and diglyceride
mixtures alone or with the addition of metallic soaps,
such as, aluminum stearate. The metallic soaps appear
to~ improve the characteristics of some of the
emulsion. Additional emulsifiers present in the
hydrophobic phase may also be selected from the group
consisting of sorbitan esters, lecithin, 1 to 5 mole
ethoxylates of fatty acids or alcohols, saccharides
derivatives and mixtures thereof.
35- ~ In a further embodiment of the invention, a
method is provided for treating an oral or esophageal
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disorder, or for providing for the absorption of an
active material for a systemic effect in an animal
which comprises administering to the oral cavity a
therapeutically effective amount of a solid or semi-
s solid bioadherent, orally ingestible system, which
comprises: a water-in-oil system having at least two
phases, one phase comprises from about 25% to about
75% by volume of an internal hydrophilic phase the
other phase comprises from about 25% to about 75% by
volume of an external hydrophobic phase is comprised
of at least three components, one component being
about 5% to about 50% of an emulsifier, a second
component being about 0% to about 75% of a mixture of
glyceride esters of long chain fatty acids and a third
component being about 10% to about 50% of a wax
material having a melting point within the range of
about 50°C to about 200°.
In a further embodiment, a chewing gum
composition is provided for delivering the emulsions
of this invention to the oral cavity which comprises
a medicated chewing gum composition, which comprises:
a) a gum base in an amount sufficient to form a
chewing gum composition; b) effective amount of
chewing gum additives to soften the gum base; and, c)
an effective amount of an active pharmaceutical
composition dispersed within a water-in-oil emulsion
system having at least two phases, one phase comprises
from about 25% to 75% by volume of an internal
hydrophilic phase and the other phase comprises from
abut 25% to about 75% by volume of an external
hydrophobic phase, wherein the external hydrophobic
phase is comprised of three components, a) one
component being about 5% to about 50% of an
emulsifier, b) a second component being about 10% to
about 75% of a mixture of glyceride esters of long
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chain fatty acids and c) a third component being about
lOg to about 50~ of a wax material.
In another embodiment, a confectionery
composition is provided for delivering the emulsions
of this invention to the oral cavity which comprises
a medicated confectionery composition, which
comprises: a) a confectionery composition; and, b) an
effective amount of an active pharmaceutical
composition~dispersed within a water-in-oil emulsion
system having at least two phases, one phase comprises
from about 25% to about 75% by volume of an internal
hydrophilic phase and the other phase comprises from
about 25% to about 75% by volume of an external
hydrophobic phase, wherein the external hydrophobic
phase is comprised of three components, a) one
component being about 5% to about 50% of an
emulsifier, b) a second component being about 10 to
about 75% of a mixture of glyceride esters of long
chain fatty acids and c) a third component being about
IO to about 50° of a wax material.
DETAILED DESCRIPTION OF T8E INVENTION
The present invention provides an orally.useable
emulsion or suspension in solid or semi-solid form.
Preferably the system liquifies when taken orally at
body temperatures and is taken orally for the purpose
of coating the mouth cavity, esophageal, pharynx
tissue and/or GI tract membranes. Alternatively, the
emulsion is delivered in a suitable pharmaceutical
carrier, chewing gum composition, confectionery
composition, or other acceptable carrier vehicle.
When the emulsions are used directly or in a
carrier, they are intended to remain in place for
extended periods of time and can serve as a reservoir
for the delivery of drug or pH modifying ingredients.
The property common to all formulations of this
invention is the coating and adhering of the system to
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mucosal membranes of the mouth, pharynx, esophagus
and/or GI tract for extended periods of time,
independent of the form in which they are delivered.
The formulations coat and protect membranes of
the mouth, pharynx, esophagus and/or GI tract, while
promoting healing of esophagitis and ulcers as well as
other disorders. The resulting protective layer also
has the potential to provide a reservoir of drugs or
pH modifying ingredients.
The formulations may contain an extended release
buffer for controlling pH over an extended period of
time by prolonged stomach residence through adhesion
to the esophagus and villi as well as through
swelling and resisting pylorus dumping. In addition,
the film layer, which is amorphous in structure when
adhered to biological tissue, continually adjusts
itself with organ musculature creating a symbiotic,
therapeutic system residing for extended periods of
time in the target issue, such as in the mouth,
esophagus, pharynx and/or stomach. Because of the
unique emulsion system, the protective film has the
potential to increase in thickness as time goes on by
absorption of resident fluids into the hydrophilic
layer of the system. This can then provide a thicker
layer as a protectant. In contrast, prior art polymer
systems have the potential to wash away quickly.
As discussed, the bioadherent system of this
invention is able to adhere to the mucosa for long
periods of time. During adherence, the system absorbs
moisture and_enables the drug to be transported across
the epithelial tissue. Adherence occurs for from 30
minutes to 24 hours and preferably 2 to 8 hours. it
has been calculated that by using the system of this
invention a diffusion matrix is formed which enables
the transport of biologically active material from the
~~ V lVIVVI I V
1 ~ I'~ i ~ ,.~
system through the epithelial tissue in less than 2
hours and preferably from 50 minutes to 2 hours.
While not being bound by any particular theory of
activity, it is believed that the present bioadhesion
system enables sufficient active ingredient to diffuse
~ from the BIOADHESIVE substrate through the oral or
esophageal epithelium and through and into the
vasculature of the capillary beds present within the
oral and esophageal mucosa. These capillary beds have
direct access to and are drained into the general
systemic circulation of fluids within the body
including plasma, serum, lymph and blood.
A distinct advantage of using a bioadhesive
substrate on the oral and esophageal mucosa is to
effect the systemic circulation of sufficient active
agents resulting from an oral administration of the
active agent/drug delivery system to the oral cavity
and esophagus. In this manner, biologically sensitive
material may be administered orally, which has not
been possible heretofore.
In conventional treatments, biologically
sensitive material, such as proteins and hormones are
administered by direct injection or infusion directly
into the systemic circulation because the active drug
is essentially digested and destroyed after
introduction to the gastrointestinal tract. In the
present bioadhesive delivery systems, the active drug
is delivered in a protected manner that is not hostile
to_the active drug and, yet, due to the bioadhesive
nature of the drug delivery platform, allows
sufficient retention time at the site of absorption
for sufficient absorption of the active drug.
Further, incorporation of the active drug in the
bioadhesive delivery system is expected to stabilize
the active drug from both chemical and physical
degradation.
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The phrase "oral disorders" or "dental
disorders," relates to disorders of the lips, mouth
and tongue including buccal mucosa, salivary glands,
palate and stomatitis; dental caries including pulpits
5 and periapical abscess; periodontal disease including
gingivitis and periodontitis; temporomandibular joint
disorders; neoplasms of tissue; and dental emergencies
including toothache, fractured and avulsed teeth, and
so forth.
10 The phrase "pharynx, esophageal and/or GI tract
disorders" relates to those disorders found in the
pharynx, esophagus, functional dyspepsia and from
other nonspecific gastrointestinal complaints,
gastrointestinal bleeding, disorders of the esophagus,
stomach, and duodenum, acute abdomen and surgical
gastroenterology, diarrhea and constipation,
gastroenteritis, inflammatory diseases of the bowel
and so forth.
Specific nonlimiting disorders that are treatable
by the emulsions of this invention include the
following:
Pre-esophageal dysphagia; esophageal dysphagia;
gastroesophageal reflux; corrosive esophagitis and
stricture such as
a) esophageal diverticula
b) hiatus hernia (or gastroesophageal
reflux disease (GERD))
c) esophageal laceration and rupture, and
d) infectious disorders of the esophagus;
functional dyspepsia; nausea and
vomiting; globus sensation; adult
rumination; halitosis, real and
imagined; arteriovenous malformations;
gastritis; peptic ulcer; neoplasms of
the stomach; abdominal pain;
peritonitis; pancreatitis; cancer of
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the pancreas; diarrhea; constipation;
gastroenteritis due to bacterial
enterotoxins; menorrhagic colitis;
staphylococcal food poisoning botulism;
malabsorption syndromes such as
i) carbohydrate intolerance
ii) celiac disease
iii) tropical spruce
iv) whipple's disease
v) intestinal lymphangiectasia and
vi) infection and infestation;
Crohn's disease; ulcerative
colitis and so forth.
Besides treating these various disorders, the
delivery system is useful in enhancing the transport
of biologically active components across the
epithelium and into the capillary beds or circulatory
structures within the epithelial mucosa. In this
manner, biologically active material which would be
rendered inactive by stomach acids or
stomach/intestinal enzymes are able to be administered
orally without need for injection. Examples of useful
compounds that may be administered in this manner
include proteins, peptides, polypeptides, hormones,
and so forth. Non-limiting examples include the human
growth hormone (hGH), insulin, tissue plasminogen
activator (tPA), calcitonin, atriaT natriuretic
factor, and erythropoietin.
The present system is composed of two phases; a
hydrophilic inner phase and a hydrophobic external
phase. More particularly, the present system
comprises a water-in-oil emulsion system having at
least two phases, one phase comprises from about 25%
to- about 75% by volume of an internal hydrophilic
phase, and preferably about 50% to about 70% by
volume. The other phase comprises from about 25% to
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about 75% and preferably about 25% to about 50% by
volume of an external hydrophobic phase. A unique
feature of the external hydrophobic phase is that it
is comprised of at least three components. One
component being about 5% to about 50% by weight of the
hydrophobic phase of an emulsifier. The second
component being about 0% to about 75% by weight of a
glyceride ester. The third component being about 10%
to about 50% by weight of a wax material.
The hydrophilic polymer phase is present in the
delivery system in amounts of about 25% to about 75%
and most preferably about 50% to about 70% by volume
of the overall system. As discussed above, the
hydrophilic polymer phase is present in amounts at
least equal to and preferably far greater than the
external hydrophobic phase and is situated to enable
the retention of active material, when used.
Preferably the hydrophilic phase is selected from
the group consisting of water, glycerine, sorbitol
solutions, sugar syrups, polymer solutions and
mixtures thereof. The hydrophilic polymer material
does not have to have any solubility in the
hydrophobic phase and is preferably selected from
water and sorbitol solutions, such as solutions
containing 70% by weight sorbitol. A wide variety of
natural polymers or derivatives thereof as well as
synthetic polymers may also be used. Exemplary
polymers include polyethylene glycol polymers having
mean average molecular weight of at least 1000 and
preferably from about 200 to 2 million or more.
Exemplary sugar syrups include corn syrup, high
fructose corn syrup and exemplary sugar solutions ,
include cane sugar solutions, dextrose solutions,
lycasin and ~~o forth.
- The hy3vophobic phase is present in the delivery
system in alounts generally less than the internal
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phase even though in some systems amounts to about 75%
are useable. In general amounts of about 25% to about
75% by volume of the system are useable with preferred
amounts of about 25% to about 40% by volume being most
preferred. The hydrophobic phase is specifically
designed to avoid the prior use of low amounts of
emulsifier and to produce a stable solid or semi-solid
emulsion which becomes flowable at body temperature.
In particular the present hydrophobic phase is
composed of at least three essential components.
In general, the hydrophobic phase is composed of
at least three components: a) an emulsifier, b) at
least one glyceride ester and c) a wax material. Hy
raising the emulsifier content in the external phase
to be about or less than SO% of the hydrophobic phase,
an adhesive formulation is prepared which will adhere
to the mouth tissue and other mucosa, tissue and GI
tract lining. The configuration of the external phase
is critical to prevent the internal phase for
coalescing and disintegrating after use. By using
relatively high levels of emulsifiers, waxes and
glyceride esters, the capability of the internal phase
to absorb aqueous components is enhanced.
Particularly preferred wax materials are selected
from animal waxes, vegetable waxes, petroleum waxes,
synthetic waxes, and mixtures thereof and include
without limitation beeswax, candelilla wax, carnauba
wax,- microcrystalline wax and mixtures thereof. The
wax materials are used in amounts of about'4% to 50%
by weight. Also the wax has a preferred melting point
within the range of about 50° to about 200°C.
The emulsifier used in the formulations of this
invention find utility for preventing the internal
. phase from coalescing and disintegrating after use.
It has the advantage of increasing the efficacy of any
dig used over that obtainable with commercial
SUBSTITUTE SKEET (RULE 20)
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formulations. Preferably, the emulsifiers are
soluble in the hydrophobic (lipoidal) or external
phase. Suitable emulsifiers are those oil miscible
surface active compounds which are acceptable for use
in foods, pharmaceuticals, and/or cosmetics. Examples
of such emulsifiers are low molecular weight
polyglycerols which have been esterified with fatty
acids or fatty acid esters, or mono and diglyceride
mixtures alone or with the addition of metallic soaps,
such as, aluminum stearate. The metallic soaps appear
to improve the characteristics of some of the
emulsions.
Particularly preferred emulsifiers have a FHB
value less than about 10 in order to obtain these
desirable features. HLE is a qualitative description
for emulsifiers wherein the ratio of hydrophile to
lipophile can be assessed. Emulsifiers with HLB's
below 10 are more lipid-soluble than water-soluble and
tend to form stable water-in-oil emulsions.
The emulsifier is preferably selected from
sorbitan esters, lecithin, 1 to 5 mole ethoxylates of
fatty acids or esters, saccharide derivatives and
mixtures thereof. particularly preferred emulsifiers
are selected from the group consisting of soy
lecithin, sorbitan monooleate, glycerol monooleate and
mixtures thereof. Examples of saccharide derivatives
include fatty acid saccharide derivatives such as
sucrose oleate and sucrose stearate. The emulsifiers
are present in the hydrophobic phase in amounts of
about 5% to about 50% by weight of this phase and
preferably in amounts of about 10% to about 30% by
weight of this phase.
The glyceride esters are preferably selected from
a.blend of mono-, di-, and triglyceride esters of long
chain fatty acids and most preferably fatty acids
having straight or branched chain alkyls containing 10
SUBS T i T UTE SN~ET (RULE 26)
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. r
to 32 carbon atoms. Specific examples of fatty acids
include, lauric, myristic, palmitic, stearic, oleic,
linoleic and linolenic acids. Combinations of
glyceride esters are preferably used in the present
5 formulations in order to produce products having the
desired solid or semi-solid texture and stable
emulsion properties. The glyceride esters are
employed in amounts up to 750, that is about 0% to
about 75% of the hydrophobic phase. The glyceride
10 esters also have preferred melting points between
about 3 0° and about 5 0°C .
In addition to the noted component parts of the
hydrophobic layer, this layer may also include other
components to aid in the formation of the water-in-oil
15 emulsions of this invention. Such components may
include diluents as well as other excipients; binders
such as ethylcellulose, sodium carboxymethyl
cellulose, polyvinylpyrrolidone; and the like.
The formulations viscosities are prepared to have
a solid to semi-solid consistency, that is they may
range from being solid to having a semi-thick
consistency. Solid emulsion formulations that liquify
at body temperature are desirable where portability
and ease of use by a patient are important. When
using solid or semi-solid viscosities it is important
that after the formulation is taken orally for it to
start to exhibit a flow character to enable coating of
the oral cavity, esophagus, pharynx and GI tract.
The overall degree of hardness, tack and melting
point is controlled primarily by the blending of the
external phase components, and to a lesser degree by
the amount of dissolved species in the internal phase.
A certain degree of plasticity is also required in the
external phase, otherwise the finished product will
crack and weep rather easily. Plasticity is usually
achieved by incorporating appropriate amounts of lipid
PCTIUS95/09483
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16
soluble oils and liquid surfactants. The main types
of ingredients used to control the overall melting
point and hardness are the hard fats (mostly
triglycerides, but some mono and diglycerides), waxes
(paraffin, microcrystalline, vegetable, mineral and
animal), fatty alcohols and acids and fatty acid
esters. These techniques are well known in
formulating solids that melt at body temperatures.
The formulations of the invention may be used as
is when preblended with an active material or drug
when being prepared. While not being limited thereto,
water-soluble drugs are preferably used in the
hydrophilic internal phase whereas water-insoluble
drugs are present in the external hydrophobic phase.
The active materials) or drugs) may be
described as a single drug entity or a combination of
entities. The delivery system is designed to be used
with drugs having high water-solubility as well as
with drugs having low water-solubility to produce a
2o drug delivery system that has controlled release
rates. The term "drug" includes without limitation,
medicaments, vitamins, mineral supplements and other
chemical or biological substances intended for use in
the treatment, prevention, diagnosis, cure or
mitigation of disease or illness of the oral cavity
and gastrointestinal tract or substances which affect
the structure of function of the oral cavity,
esophagus and gastrointestinal tract body; all herein
referred to as a "disorder."
Suitable categories of drugs that may be employed
in the instant application may vary widely and
generally represents any stable drug or combination _
thereof. Exemplary nonlimiting examples include:
Expanded Therapeutic Categories _
' Anabolic agents
Antacids
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Anti-asthmatic agents
Anti-cholesterolemic and anti-lipid agents
Anti-coagulants
Anti-convulsants
Anti-diarrheals
Anti-emetics
Anti-infective agents
Anti-inflammatory agents
Anti-manic agents
Anti-nauseants
Anti-obesity agents
Anti-pyretic and analgesic agents
Anti-spasmodic agents.
Anti-thrombotic agents
Anti-uricemic agents
Antianginal agents
Antihistamines
Antitussives
Appetite suppressants
Biologicals
Cerebral dilators
Coronary dilators
Decongestants
Diuretics
Erythropoietic agents
Expectorants
Gastrointestinal sedatives
Hyper-glycemic agents
Hypnotics
Hypo-glycemic agents
Ion exchange resins
Laxatives
Mineral supplements
Mucolytic agents
Neuromuscular drugs
Peripheral vasodilators
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Psychotropics
Sedatives
Stimulants
Thyroid and anti-thyroid agents
Uterine relaxants
Illustrative categories and specific examples
include: (a) antitussives, such as dextromethorphan,
dextromethorphan hydrobromide, noscapine,
carbetapentane citrate, and chlophedianol
l0 hydrochloride; (b) antihistamines, such as
chlorpheniramine maleate, phenindamine tartrate,
pyrilamine maleate, doxylamine succinate, and
phenyltoloxamine citrate; (c) decongestants, such as
phenylephrine hydrochloride, phenylpropanolamine
hydrochloride, pseudoephedrine hydrochloride,
ephedrine; (d) various alkaloids, such as codeine
phosphate, codeine sulfate and morphine; (e) mineral
supplements such as potassium chloride, zinc chloride
and calcium carbonates, magnesium oxide and other
alkali metal and alkaline earth metal salts; (f)
laxatives, vitamins and antacids (g) ion exchange
resins such as cholestryramine; (h) anti-
cholesterolemic and anti-lipid agents; (i)
antiarrhythmics such as N-acetylprocainamide; (j)
antipyretics and analgesics such as acetaminophen,
aspirin and ibuprofen; (k) appetite suppressants such
as phenylpropanolamine hydrochloride or caffeine; (1)
expectorants such as guaifenesin; (m) antacids such as
aluminum hydroxide and magnesium hydroxide; (n)
biologicals such as peptides, polypeptides, proteins
and amino acids, hormones, interferons and other
bioactive peptididic compounds, such as hGH, tPA, _
calcitonin, ANF, EPO and insulin; and (o) anti-
infective agents, such as antifungals, anti-virals,
35- antiseptics and antibiotics.
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The drugs are used in amounts that are
therapeutically effective. While the effective amount
of a drug will depend on the drug used, amounts of
drug from about 5% to about 65% have been easily
incorporated into the present delivery systems while
achieving controlled release. Lesser amounts may be
used to achieve efficacious levels of treatment for
certain drugs.
The systems may be prepared by continuous or
batch processes. As in preparing conventional
emulsions, shear force is applied to the system
components by use of homogenizers, mills, impingement
surfaces, ultra-sound, shaking or vibration. Unlike
conventional emulsions, the mixing shear should be at
low levels in order to prevent destruction of the
system by imparting excess energy. Temperature is not
usually a critical factor in the preparation of the
systems. The temperatures utilized will be dependent
upon the final end product desired.
The systems may be prepared by mixing the
internal with the external phase in a planetary-type
mixer. Another manner of preparing the system is by
use of a continuous mixer which comprises multiple
impellers. The external phase is first introduced
into the continuous mixer until it reaches the level
of the lowest impeller in the mixing chamber. The two
phases are then simultaneously introduced through the
bottom of the mixer in proper proportion as its
impeller or impellers rotate to apply a shear to the
components. The finished product emerges-through the
top of the mixer and is stored or poured into molds
and hardened. The actual speed of the impeller or
impellers will vary, depending upon the product
produced as will the rate of flow of the two phase
streams.
wo 96/o397s PGTJITS9s/09483
2~ 9~i 6~
In a preferred embodiment, the active agent or
drug and ingredients of the internal phase were mixed
together at room temperature (24°C). The ingredients
of the external phase were mixed together in a
5 separate vessel. The internal phase composition was
slowly added to the external phase composition as the
two phases are mixed together at low shear until the
desired viscosity was obtained.
It is believed that the release mechanism of
10 active components may be a combination of several
phenomena once the formulation is adhered to the oral
cavity, esophagus and pharynx membrane walls and/or GI
tract. Enzymatic degradation of the system, diffusion
of the drug through the system, competitive
15 adsorption, desorption of hydrophobic components from
hydrophilic surface centers, convection of the drug
through mesopores and macropores, diffusion of the
external medium into the system by way of solubility
or capillary action through porous structures created
20 by the addition of hydrophilic polymers or water-
soluble solids, as well as expansion of drug and/or
system from water absorption into the inner phase.
The emulsion system may also be used in
combination with one or more conventional excipients.
The term "excipients" as used in the drug or food
industry which do not alter the basic character and
function of the active component or oral system and
include flavors, sweetening agents and so forth.
The excipients are added to the oral delivery
system anytime during processing. It should be
recognized that certain excipients should be added
prior to, during or after blending of the two phases.
Generally, the emulsion is prepared by separately
making the hydrophilic and hydrophobic phases and then _
blending the phases together by adding the hydrophilic
phase to the hydrophobic phase. In a particularly
wo mo39~s 2 ~ ~ ~ ~ rc-r~os~o9as3
1~
21
preferred procedure the hydrophobic phase is prepared
by blending and melting the glyceride esters together
with the wax material. Once a homogenous blend is
obtained the emulsifier is added and blended to form
the hydrophobic phase. The hydrophilic phase is then
added in incremental amounts to the hydrophobic phase
while mixing the components. As more and more of the
aqueous phase is added the product begins to thicken
to a smooth cream consistency. When the phase
combination is complete, the product can be pumped,
molded or filled into a final pharmaceutically
acceptable carrier.
The emulsion once prepared may be stored for
future use or formulated with conventional additives,
that is pharmaceutically acceptable carriers, to
prepare compositions which offer a variety of
textures to suit particular applications. Such
compositions may be in the form of a lozenge, tablet,
toffee, nougat, chewy candy, oral hygiene
preparations, breath fresheners and other oral
applications and suspensions and so forth.
The pharmaceutically acceptable carriers may be
prepared from a wide range of materials. Without
being limited thereto, such materials include
diluents, binders and adhesives, lubricants,
disintegrants, colorants, bulking agents, flavorings,
sweeteners and miscellaneous materials such as buffers
and adsorbents in order to prepare a particular
medicated composition.
The preparation of confectionery and chewing gum
products containing the present emulsions is also
contemplated. When used in such systems, the
formulations of this invention may be blended with the
confectionery or chewing gum product, coated on the
surface thereof or even center filled, to enable the
active component to be administered.
wo mo3rrs ~ 1 ~ ~. ~ ~ ~ PGT/US95/09483
22
As used herein, the term confectionery material
means a product containing a bulking agent selected
from a wide variety of materials such as sugar, corn
syrup and in the case of sugarless bulking agents
sugar alcohols such as sorbitol and mannitol and
mixtures thereof. Confectionery material may include
such exemplary substances as lozenges, tablets,
toffee, nougat, chewy candy and so forth. In general,
the bulking agent will comprise from about 5% to about
99% and preferably 20% to about 95% by weight of the
medicated confectionery product.
Lozenges are flavored medicated dosage forms
intended to be sucked and held in the mouth. They may
be in the form of various shapes, the most common
being flat, circular, octagonal and biconvex forms.
The lozenge bases are generally in two forms, hard,
boiled candy lozenges and compressed tablet lozenges.
The hard boiled candy lozenges are prepared from
a mixture of sugar and other carbohydrates that are
kept in an amorphous or glassy condition. This form
can be considered a solid syrup of sugars generally
having from 0.5% to about 1.5% moisture. Such
materials normally contain up to about 92% corn syrup,
up to about 70% sugar and from 0.1% to about 5.0%
water. The syrup component generally is prepared from
corn syrups high in dextrose, but may include other
materials. Further ingredients such as flavorings,
sweeteners, acidulents, colorants and so forth may
also be added.
Boiled candy lozenges may also be prepared from
nonfermentable sugars such as sorbitol, mannitol and
hydrogenated corn syrup. The candy lozenges may
contain up to about 95% sorbitol, a mixture of
sorbitol and mannitol at a ratio of about 9.5 to 0.5
wp~to about 7.5 to 2.5 and hydrogenated corn syrup up
to about 55% of the syrup component.
WO 96103975 ~ ~ ~' PCT/US95I09483
23
In contrast, compressed tablet lozenges contain
particulate materials and are formed into structures
under pressure. They generally contain sugars in
amounts up to 95o and typical tablet excipients such
as binders and lubricants as well as flavors,
colorants and so forth.
The lozenges may be made of soft confectionery
materials such as those contained in nougat. These
materials contain two primary components, namely a
l0 high boiling syrup such as corn syrup or the like, and
a relatively light textured frappe, generally prepared
from gelatin, egg albumen, milk proteins such as
casein, and vegetable proteins such as soy protein and
the like. The frappe is generally relatively light,
and may, for example, range in density from about 0.5
to about 0.7 g/cc.
By comparison, the high boiling syrup, or "bob
syrup," is' relatively viscous and possesses a higher
density and frequently contains a substantial amount
of sugar. Conventionally, the final nougat
composition is prepared by the addition of the "bob
syrup" to the frappe under agitation, to form the
basic nougat mixture. Further ingredients such as
flavorings, oils, additional sugar and the like may be
added thereafter also under agitation. A general
discussion of the composition and preparation of
nougat confections may be found in B. W. Minifie,
CHOCOLATE, COCOA AND CONFECTIONERY: Science and
Technolocrv, 2nd edition, AVI publishing Co., Inc.,
Westport, Conn., (1980), at 15 pages 424=425, which
discloses is incorporated herein by reference.
Unlike lozenges, nougat formulations are prepared
by admixing the nougat candy base with the remaining
ingredients, including active formulations of this
invention, until a homogenous admixture is obtained
and then forming the resulting mixture into suitable
WO 96/03975 L ~ ~ ~ ~ PCT/US95/09483
24
shapes for storage. The preparation of the nougat
candy base may be achieved by routine procedures well
known to the ordinary skilled artisan. One preferred
procedure involves the preparation of a whipping
component and blending with it a syrup component.
See, for example, U.S. Patent 4, 683, 138 to Glass et
al.
The whipped component may be prepared by mixing
the whipping agent with other desirable components.
The whipped component is generally prepared from
gelatin, egg albumen, milk proteins such as casein,
and vegetable proteins such as soy protein, and the
like which are added to a gelatin solution and rapidly
mixed at ambient temperature to form an aerated sponge
like mass.
The syrup component is prepared by initially
mixing corn syrup, sugar component and an amount of
water necessary to assure solution of the ingredients.
The total water content is not critical, however, it
is preferable to keep the initial water content below
40% by weight. This mixture is charged into a
suitable cooker and cooked to a final water content of
about 2% to about ll.Oo by weight.
Once the above steps are complete, the whipped
component and the syrup component may be combined,
usually by the addition of whipped component to the
syrup component after the syrup component's
temperature has dropped to about 110°C. to about 188°C.
The resultant combination is then mixed. At this
point, an edible polyol may be added. If colorants
are to be incorporated, they may be incorporated into
the candy base at this point. The composition is then
mixed until a uniform homogenous mass is formed.
The emulsions of this invention may then be added
and mixed until a uniform homogenous mass is formed.
If fats are to be incorporated, they are incorporated
WO 96103975 ~ ; ~ ~ ~j PCT/US95/09483
into the candy base at this time. The above
composition is mixed until the temperature of the
composition is less than about 90° C. but greater than
60° C. At this point, a graining compound, if
5 employed, is added to the composition. If flavorings
are to be incorporated, they may be added into the
candy base also at this time. The mixture is then
further mixed until uniform.
Once all of the reagents have been blended into
10 the mixture, the mixture is allowed to cool. The
mixture may be cooled to ambient temperatures before
final forming operations are completed.
A variety of final forming techniques may be
utilized, depending upon the shape and size of the
15 final product as desired.
Once prepared the final composition may be
processed into any desirable shape or form to render
the product suitable for providing the necessary
amount of mineral compound. Exemplary, non-limiting
20 shapes include squares, rectangles, spheres, tabloids
and biconvex shapes. Other suitable shapes may also
be employed.
In the practice of this invention, a conventional
chewing gum composition of the prior art may be used
25 to assist in the delivery of the emulsions of this
invention. The emulsions may be blended in the
chewing gum composition, serve as a coating layer
thereon or even be center-filled within the chewing
gum composition.
Without being limited to specific chewing gum
formulations, exemplary examples are described in U.S.
Patent 4,775,537 and 4,683,138. These formulations
generally contain a gum base and modifiers to form an
acceptable texture and sweetness.
. The gum base compositions may contain
conventional elastomer solvents to aid in softening
WO 96/03975 ~ '~ C ~ '~ ~ ~ PCT/US95109483
26
the rubber component. Such elastomer solvents may
comprise methyl, glycerol or pentaerythritol esters of
rosins or modified rosins, such as hydrogenated,
dimerized or polymerized rosins or mixtures thereof.
Examples of elastomer solvents suitable for use herein
include pentaerythritol ester of partially
hydrogenated wood or gum rosin, pentaerythritol ester
of wood or gum rosin, glycerol ester of partially
dimerized rosin, glycerol ester of polymerized rosin,
l0 glycerol ester of tall oil rosin, glycerol ester of
wood or gum rosin and partially hydrogenated wood or
gum rosin, and partially hydrogenated methyl ester of
rosin and mixtures thereof. The elastomer solvent may
be employed in an amount ranging from about 10% to
about 75% and preferably about 45°s to about 70% by
weight of the gum base.
A variety of traditional ingredients used as
plasticizers or softeners such as lanolin, stearic
acid, sodium stearate, potassium stearate, glycerol
triacetate, glycerin, lecithin, and glycerol
monostearate and the like, may also be incorporated
into the gum base to obtain a variety of desirable
textures and consistency properties. These additional
materials are generally employed in amounts of up to
about 30% by weight and preferably in amounts of from
about 3% to about 5% by weight of the final gum base
composition.
The chewing gum compositions may also employ
sweetening agents (sweeteners). The sweetening agent
may be selected from a wide range of materials
including water-soluble sweetening agents, water-
soluble artificial sweeteners, water-soluble
sweetening agents derived from naturally occurring
water-soluble sweeteners, dipeptide based sweeteners, ,
and protein based sweeteners, including mixtures
thereof .
WO 96103975 PGT/US95/09483
G~ ~t~~ ~r~
27
The chewing gum compositions may additionally
include effective amounts of the conventional
additives of coloring agents such as titanium dioxide;
emulsifiers such as lecithin and glycerol
monostearate; maltodextrins; and fillers such as
aluminum hydroxide, alumina, aluminum silicates, talc,
dicalcium phosphate, calcium carbonate, and
combinations thereof. Preferably the amount of
fillers used is up to about 25% by weight of the gum
base.
The chewing gum compositions may be produced by
techniques well known to those skilled in the art.
For example, using conventional equipment the gum base
is heated to temperatures sufficiently high enough to
soften the base without adversely effecting the
physical and chemical make up of the base. The
optimum temperatures utilized may vary depending on
the composition of the gum base used, but such
temperatures are readily determined by those skilled
in the art without undue experimentation. For
example, suitable temperature for softening the gum
base are within the range of about 70° C. to about 90°
C. Temperatures within the range of about 40° C. to
about 60° C. may be used when the gum base used is
amongst those disclosed in, for example, U.S. Pat. No.
4,587,125. During heating, the gum base is mixed with
any of the optional components traditionally used with
the gum base, such as plasticizers and elastomer
solvents. In general, the order of addition of the
various components (ingredients) of the -chewing gum
composition is not critical. The flavoring agents,
however, should be added when the gum base has been
allowed to cool to a temperature below the
volatilization temperature of the flavoring agents
used. The flavors may be added separately or blended
together as a preblend before their addition. The
2~~~~tl~
28
mixture so produced is then extruded, using
conventional equipment, and formed into suitable
chewing gum shapes. The emulsions of this invention
may also be added during the formation of the gum
5 product or after it is formed either before or after
the flavors are blended in the chewing gum
composition.
Regarding center-filled gum, the emulsions of
this invention may be pumped into the center-fill into
10 a hollow-centered rope of chewing gum and then cut
into pieces. The center-filled emulsion is then
released upon chewing the gum composition resulting in
release of the emulsion into the oral cavity.
Pharmaceutical emulsions or suspensions of this
15 invention may also be prepared by conventional methods
long established in the art of pharmaceutical
compounding. The oral formulations may also contain
conventional adjunct or excipient materials.
Representative examples include the following
20 materials:
(a) Preservatives such as benzoic acid, sorbic
acid, methylparaben, propylparaben and
ethylenediaminetetraacetic acid (EDTA). Preservatives
are generally present in amounts up to about 1 % and
25 preferably from about 0.05% to about 0.5% by weight of
the suspension;
(b) Buffers such as citric acid-sodium citrate,
phosphoric acid-sodium phosphate, and acetic acid-
sodium acetate in amounts up to about 1% and
30 preferably from about 0.05% to about 0.5% by weight of
the suspension;
(c) Suspending agents or thickeners such as -
cellulosics like methylcellulose, carageenans like
alginic acid and its derivatives, xanthin gums, .
35 gelatin, acacia, and microcrystalline cellulose in
WO 96/03975 ~ ~ ~~ ~ 1 ~ ,.~3 PCT/OS95/09483
29
amounts up to about 20% and preferably from about 1%
to about 15% by weight of the suspension;
(d) Antifoaming agents such as dimethyl
polysiloxane in amounts up to about 0.2% and
preferably from about 0.01% to about 0.1% by weight of
the suspension;
(e) Sweeteners include those sweeteners both
natural and artificial well known in the art;
(f) Flavorants include both natural and
artificial flavors, and mints such as peppermint,
menthol, vanilla, artificial vanilla, chocolate,
artificial chocolate, cinnamon, various fruit flavors,
both individual and mixed may be utilized in amounts
from about 0.5% to about 5% by weight of the
suspension;
(g) Colorants useful in the presentation
invention include pigments which may be incorporated
in amounts of up to about 6% by weight of the
composition. A preferred pigment, titanium dioxide,
may be incorporated in amounts up to about 1%. Also,
the colorants may include other dyes suitable for
food, drug and cosmetic applications, and known as
F.D.&C. dyes and the like. Such dyes are generally
present in amounts up to about 0.25% and preferably
from about 0.05% to about 0.2% by weight of the
suspension;
(h) Decolorizing agents such as sodium
metabisulfite, ascorbic acid and the like may be
incorporated into the suspension to prevent color
changes due to aging. In general, amounts up to about
0.25% and preferably 0.5% to 0.2% by weight of the
suspension are used; and
(i) Solubilizers such as alcohol, propylene
glycol, polyethylene glycol and the like may be us ed
to solubilize the flavors. Solubilizing agents a re
WO 96/03975 ~
~ 1 a .~. ~ ~~ ~ rcrms9s~o9as3
:; 3 0
generally present in amounts up to 10%; preferably
from about 2% to about 5% by weight of the suspension.
Pharmaceutical tablets of this invention may also
be in chewable form. This form is particularly
advantageous because of convenience and patient
acceptance. To achieve acceptable stability and
quality as well as good taste and mouth feel several
considerations are important, namely amount of active
substance per tablet, flavor, compressibility and
organoleptic properties of the drug.
The formulations may also be formulated with
conventional well known ingredients to form lip balm
or components of lipstick to aid in delivery of the
active component present in the emulsion.
The following examples are illustrative of
preferred embodiments of the invention and are not to
be construed as limiting the invention thereto. All
percentages of the two phases are based on volume
whereas percentages of phase components are based on
the percent by weight of the phase unless otherwise
indicated and all totals equal 100% by weight.
EXAMPLE 1
This example describes the preparation of a solid
stable oral pharmaceutical preparation.
Formulation Components Weicrht
Mineral Oil 1.9
Di and triglyceride esters having
melting point 33.5-35.5'C 7.1
Mono-, Di-, and triglyceride esters
having melting point 33.5-35.5'C 7,1
Triglyceride esters having melting -
point 42-44'C 3.67
Microcrystalline wax 0.92
Beeswax 4.55
Sorbitan monooleate 6.83
Glycerol Monooleate 0.83
Soy Lecithin 2.5
F1-avor 0 . 3
Methyl and propyl parabens
.03
Water 61.89
Sorbitol 70% Solution 2.38
WO 96!03975 ~ ; ~ ~ ~ PCT/US95/09483
v
31
Procedure
1) Water and Sorbitol solution are weighed into a
suitable container and stirred until uniform and then
warmed to 50-55'C.
2) In a separate container the glyceride esters were
melted with the beeswax and mineral oil. Beeswax
melts at 89'C, however in the presence of the other
components it can incorporate itself into the mixture
at a lower temperature.
3) Once the components of step 2 are melted, add the
parabens and microcrystalline wax. Heat to at least
65'C to melt beeswax. Once the wax is melted
uniformly, allow blend to cool to 50-55'C.
4) To the melt of step 3 add the following in order
making sure each is dissolved or evenly mixed before
adding the next component. Soy lecithin, glycerol
monooleate and sorbitan monooleate. When complete
adjust temperature to 50-55'C.
5) Immediately before the combination of the
hydrophobic phase and water phases add the flavor to
the phase it is most soluble in.
6) With moderate stirring add the aqueous phase to
the wax phase slowly. Maintain 50-55'C temperature
throughout this operation. As more and more of the
aqueous phase is added the product should begin to
thicken to a smooth cream.
7) When phase combination is complete and the
temperature is 50-55'C the product can be pumped,
molded or filled into the final product form, then
allowed to cool and become hard.
The product when mixed with various drugs and
taken orally, adhered to the oral mucosa and
esophageal mucosa. The product remained in place for
from 30 minutes to 24 hours. In this time period,
sufficient active ingredient diffused from the
substrate through the oral and esophageal epithelium
WO 96/03975 ~ ~ ~ ~ ' J ~ PCT/IJS95109483
32
and into the vasculature to obtain efficacious levels
of the drug.
EXAMPLE 2
This example describes the preparation of a
solid, cough suppressant lozenge.
Formulation Comr~onents Weight
Water 64.609
Fructose 3.544
Sodium Saccharin 0.162
Medium chain triglyceride oil 1.789
Di and triglyceride esters having a
melting point of 33.5 - 35.5 deg. C 5.176
Mono-, di- and triglyceride esters
having a melting point of 33.5-35.5
deg. C 5.176
Triglyceride esters having a melting
point of 42-44 deg. C 7.139
Microcrystalline wax 0.894
Methyl and propylparabens 0.136
Beeswax 4.418
Sorbitan Monooleate 0.809
Distilled monoglyceride p,80g
Soy Lecithin 2.427
Menthol/Eucalyptus flavor 2.912
Tota1:100.000
Procedure:
1) The water, fructose and sodium saccharin were
weighed into a suitable container, stirred until the
solids were dissolved then warmed to 50-55 deg. C.
2) The medium chain triglyceride oil, glyceride
esters and microcrystalline wax were weighed into a
separate container and warmed to 90 deg. C to melt the
solid components.
3) The soy lecithin was added to the container from
Step 2 and stirred until dissolved at a temperature of
90 deg. C.
4) The temperature of the solution was allowed to
begin cooling down to 50-55 deg. C. The
methylparaben, propylparaben and beeswax were added to
the container from Step 3 and stirred until dissolved.
1
WO 96/03975 ~ ~ ~ ~ l ~ ~ PCTIUS95/09483
33
5) The sorbitan monooleate and distilled
monoglyceride were added to the container from Step 4
and stirred until dissolved.
6) At a temperature of 50-55 deg. C one third of the
flavor was added to the container and stirred.
7) With moderate stirring the aqueous phase was
slowly added to the oil phase. The temperature Was
maintained at 50-55 deg. C. throughout this operation.
As more and more of the aqueous phase was added the
product began to thicken to a smooth cream.
8) When the phase combination was complete, the
remaining two thirds of the flavor was added and
stirred until uniformly distributed.
9) At a temperature of 50-55 deg. C. the product can
be pumped molded or filled into the final product form
then allowed to cool and become hard.
EXAMPLE 3
The oral preparation of Example 1 can be used
with human growth hormone wherein the hormone is added
to the inner phase (Step 1) in amounts of about 0.01%
to about 2 . 0% by weight . Human growth hormone is a
single poly-peptide chain of 191 amino acids having a
molecular weight of 22,124, having the empirical
formulation of C99o Hiszs Nzs3 ~2g9 S" also known as hGH,
somatotropin and human growth hormone. When consumed
orally, the preparation would be expected to adhere to
the oral and esophageal mucosa for 2 to 8 hours with
diffusion of the drug being completed within the first
two hours of use.
EXAMPLE 4
The procedure of Example 3 can be repeated with
0.01% to 2.0% tissue plasminogen activator. tPA, also
known as fibrinokinase, molecular weight approximately
70,000, described as a peptiditic human therapeutic
agent used to prevent the formation of fibrin clots or
dissolve fibrin clots. When consumed orally, the
PCTIITS95/09483
wo 9s~o3m5 ~ 1 ~ ~ ~~
34
preparation would be expected to adhere to the oral
and esophageal mucosa for 2 to 8 hours with diffusion
of the drug being completed within the first two hours
of use .
EXAMPLE 5
The procedure of Example 3 can be repeated with
0.00001% to 0.1% calcitonin added to the emulsion
system. Calcitonin, also known as thyrocalcitonin, or
TCA, molecular weight approximately 4,500, is a
l0 naturally occurring hormone secreted from mammalian
thyroid gland. When consumed orally, the preparation
would be expected to adhere to the oral and esophageal
mucosa for 2 to 8 hours with diffusion of the drug
being completed within the first two hours of use.
EXAMPLE 6
The procedure of Example 3 can be repeated with
0.0001% to 0.1% ANF added to the emulsion system.
Atrial natriuretic factor, also known as atriopeptin,
or ANF, is a potent peptide or mixture of homologous
peptides derived from the atrium of mammalian heart
and is involved in the hormonal regulation of fluid
volume and blood pressure. ANF is composed of 21-33
specific amino acids having a molecular weight of
approximately 4,000. When consumed orally the
preparation would be expected to adhere to the oral
and esophageal mucosa for 2 to 8 hours with diffusion
of the drug being completed within the first two hours
of use .
EXAMPLE 7
The procedure of Example 3 can be repeated with
O.OOlo to 0.1% Erythropoietin added to the emulsion
system. Erythropoietin, also known as erythropoiesis ,
stimulating factor, EPO, or epogen, is a glycoprotein
which stimulates red blood cell formation, produced ,
mainly in -thc~' kidneys of mammals, and has been
recently produced by genetic engineering. When
WO 96/03975 ~ ~ C.) ~' J ~ . PCT/US95I09483
_, 3 5
.: consumed orally, the preparation would be expected to
adhere to the oral and esophageal mucosa for 2 to 8
hours with diffusion of the drug being completed
within the first two hours of use.
The invention being thus described, it will be
obvious that the same may be varied in many ways.
Such variations are not to be regarded as a departure
from the spirit and scope of the invention and all
such modifications are intended to be included within
the scope of the following claims.
