U.S. patent number 3,832,460 [Application Number 05/126,256] was granted by the patent office on 1974-08-27 for anesthetic-vasoconstrictor-antihistamine composition for the treatment of hypertrophied oral tissue.
Invention is credited to Carl M. Kosti.
United States Patent |
3,832,460 |
Kosti |
August 27, 1974 |
ANESTHETIC-VASOCONSTRICTOR-ANTIHISTAMINE COMPOSITION FOR THE
TREATMENT OF HYPERTROPHIED ORAL TISSUE
Abstract
A composition for the treatment of hypertrophied and
hyperplastic oral tissue and the pain phenomena associated with
this condition. The composition contains as essential ingredients
thereof one or more alkaloids, such as the sympathomimetic amines,
which are vasoconstrictors and effect vasoconstriction of the oral
tissue, an antihistaminic agent which interfers with the access of
histamine to the endothelial cells of the capillary membrane, and a
topical anesthetic to relieve pain.
Inventors: |
Kosti; Carl M. (Bloomfield
Hills, MI) |
Family
ID: |
22423843 |
Appl.
No.: |
05/126,256 |
Filed: |
March 19, 1971 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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829793 |
Jul 2, 1969 |
3574859 |
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742535 |
Jul 5, 1968 |
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Current U.S.
Class: |
424/54 |
Current CPC
Class: |
A61K
6/20 (20200101); C08L 1/28 (20130101); C08L
5/00 (20130101); C08L 5/00 (20130101); C08L
1/286 (20130101); C08L 1/286 (20130101); C08L
1/28 (20130101); A61K 6/69 (20200101); A61K
8/4946 (20130101); A61K 6/20 (20200101); A61K
6/20 (20200101); A61K 6/20 (20200101); A61K
9/0056 (20130101); A61K 8/41 (20130101); A61Q
11/00 (20130101); A61K 6/20 (20200101); A61K
6/20 (20200101); A61K 8/44 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61K 6/02 (20060101) |
Field of
Search: |
;61K/716 ;424/49-58 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Chemical Abstracts, Vol. 65, entry 9535e, 1966..
|
Primary Examiner: Huff; Richard L.
Attorney, Agent or Firm: Dundas; Gerald P.
Parent Case Text
RELATED APPLICATIONS
This application is a continuation-in-part of my copending
application Ser. No. 829,793, filed July 2, 1969, entitled "Process
for the Treatment of Hypertrophied Gums" now U.S. Pat. No.
3,574,859, which application is a continuation-in-part of my
application Ser. No. 742,535, filed July 5, 1968, now abandoned.
Claims
I claim:
1. A composition for the treatment of hypertrophied or hyperplastic
oral tissue comprising (a) an alkaloid selected from the group
consisting of aromatic amines having between about 6 to 10 carbon
atoms and aliphatic amines having between about 4 to 7 carbon
atoms, (b) an antihistaminic component selected from the group
consisting of antazoline hydrochloride, tripelennamine
hydrochloride, tripelennamine citrate, thonzylamine hydrochloride,
methapyriline hydrochloride, methapheniline hydrochloride,
pyrilamine maleate, chlorphenamine maleate, chlorothen,
pheniramine, pheniramine maleate, chlorocyclizine hydrochloride,
diphenhydramine hydrochloride, doxylamine succinate,
phenyltoloxamine citrate, diphenylpyraline hydrochloride,
phenindamine tartrate, and thenyldiamine hydrochloride, and (c) an
anesthetic component selected from the group consisting of
secondary and tertiary amino esters of aromatic acids and secondary
and tertiary aminoacyl amides of aromatic acids, said amino esters
having the structure ##SPC12##
wherein R.sub.1 with its carbonyl group may be benzoic and paramino
benzoic acid or meta-amino benzoic acid, R.sub.2 is selected from
the group consisting of aliphatic or aromatic radicals having up to
14 carbon atoms each and R.sub.3 and R.sub.4 are selected from the
group consisting of hydrogen and aliphatic or aromatic radicals
having up to 14 carbon atoms each, and said aminoacyl amides having
the structure ##SPC13##
wherein R.sub.1 is selected from xylene or toluene, R.sub.2 is
selected from the group consisting of aliphatic or aromatic
radicals having up to 14 carbon atoms each and R.sub.3 and R.sub.4
are selected from hydrogen and aliphatic or aromatic radicals
having up to 14 carbon atoms each, said alkaloid and antihistaminic
compounds each being present in said composition in an amount of
from about 0.0125 to 5.0 per cent by weight of the composition, and
said anesthetic component being present in an amount of from about
0.0125 to 20.0 per cent by weight of the composition.
2. A composition according to claim 1 wherein said antihistaminic
compound is selected from the group consisting of antazoline
hydrochloride, diphenhydramine hydrochloride thonzylamine
hydrochloride, chlorphenamine maleate, pyrilamine maleate,
pheniramine maleate and mixtures thereof.
3. A composition according to claim 1 wherein said anesthetic
compound is selected from the group consisting of benzocaine
hydrochloride, tetracaine hydrochloride and mixtures thereof.
4. A treatment for tissue which is hypertrophied or hyperplastic
comprising applying to the area to be treated the composition of
claim 1.
5. A toothpaste composition according to claim 1 comprising said
alkaloid, anesthetic and said antihistaminic compounds, from about
0.001 to 0.5 percent of a preservative, from about 0.002 to 2.0
percent of a suspending agent and from about 1 to 21 percent of a
moisture retainer, the remainder of said composition being water
and said percentages being based on the weight of the total
composition.
6. A toothpaste composition according to claim 5 wherein said
suspending agent is selected from the group consisting of sodium
carboxymethylcellulose, methylcellulose, bentonite, acacia,
sterculia gum and tragacanth, and wherein said moisture retainer is
selected from the group consisting of glycerin, propylene glycol,
sorbital, polyethylene glycol, diethylene glycol monoethyl ether,
polysorbate, monolourate and polyoxyethylene sorbitan.
7. A composition according to claim 1 further including from about
0.001 to 0.5 weight percent of a preservative selected from the
group consisting of methylparaben, propylparaben, sodium bisulfite,
sodium benzoate, sodium thiosulfate, chlorobutanol, themersoal and
phenylmercuric acetate.
8. A mouthwash composition according to claim 7 comprising an
aqueous solution of said alkaloid, antihistaminic compound,
anesthetic compound and preservative.
9. A water soluble tablet composition according to claim 7
comprising a suspension of said alkaloid, antishistaminic compound,
anesthetic compound and preservative in a suspending agent selected
from the group consisting of sodium carboxymethylcellulose,
methylcellulose, bentonite acacia, sterculia gum and tragaconth.
Description
BACKGROUND OF THE INVENTION
Almost all practicing dentists and most physicians, especially
those in the field of neurology, otopharyngology, allergy, internal
medicine, and related specialties have at one time or another in
the normal course of their practice encountered patients exhibiting
hypertrophy or hyperplasia of the oral tissue. Enlargement in the
size of the oral tissue can be produced either by hypertrophy
(increase in the size of each cell) or by hyperplasia (increase in
the number of cells) or by both phenomena together. It is usually
difficult to differentiate clinically whether tissue is enlarged
from hypertrophy or hyperplasia or both, and for this reason the
terms are used often interchangeably. Only microscopically may the
differentiation be made.
From a clinical point of view, causes of oral tissue enlargement
can be considered of two general types of tissue and may be termed
"inflammatory hyperplasia" and "fibrous hyperplasia." At the onset
of the enlargement there is usually a true inflammatory swelling
which microscopically appears as granulation tissue containing
varying amounts of polymorphonuclear leucocytes. If the
hyperplastic process persists, there is differentiation and
proliferation of tissue cells with resultant increase in size or in
number of cells; fibrosis of tissue usually takes place, the
fibroblasts multiply rapidly, connective tissue is formed, the
inflammatory cells disappear and finally the tissue becomes
characteristic of dense, avascular tissue. Clinically this
transition is characterized by decreasing hyperemia and advancing
induration of the hyperplastic tissue. The schematic representation
of the pathologic process in transition from initiation of
inflammation to fibrosis may be illustrated
Inflammation .fwdarw. inflammatory hyperplastia .fwdarw.
Fibrous hyperplasia .fwdarw. fibrosis
The chief distinguishing clinical and microscopic signs between the
above stages are:
Inflammation is characterized with immediate dilation response of
the capillaries to the chemical or physical irritants and the
resultant changes in capillary physiology, with increase in the
number of open and dilated capillaries supplying the area and
increase in capillary filtration of fluids. This state exhibits no
cellular change nor increase in size of the tissue and is the
beginning of edema. Microscopically, there is increase in number of
leucocytes, especially polymorphonuclear neutrophils, in the tissue
fluid with no change in the cellular configuration.
Inflammatory hyperplasia is characterized with soft, hyperemic,
edematous, or cyanotic, sensitive to touch, easily bleeding tissues
which are beginning to enlarge in size clinically. Microscopically,
this condition shows an increase in the number of polymorphonuclear
nutrophils and increase in size or number of cells. The number of
open or dialated capillaries is also increased. The main feature of
this condition is the increase in size of the tissue which is
usually not present at the beginning of inflammation.
In fibrous hyperplasia the enlarged tissue is firm, dense,
insensitive, resilient, and clinically shows granular appearance.
Microscopically, the fibrous tissue is well differentiated with
many young fibroblasts present. There is decreased in number of
polymorphonuclear neutrophils and open capillaries; the epithelium
is slightly hyperplastic and mildly hyperkeratous and hornified.
Lamina propria, the submucous layel below the epithelium, shows
proliferation of the fibroblasts among which inflammatory cells are
present.
Fibrosis is a condition characterized with firm, nodular, fibrous
connective tissue. Microscopically, the picture is one of
avascular, extremely differentiated bundles of fibrous material
with no inflammatory cells or open capillary present, or very few
at best, in the tissues.
It becomes apparent now that inflammation and hyperplasia or
hypertrophy are different and distinct conditions with inflammation
at times, especially at the onset of the pathologic process, being
associated with hyperplasia or hypertrophy, inflammation being
secondary to hyperplasia or hypertrophy. Hyperplasia or hypertrophy
is always manifested in enlargement of tissue whereas inflammation
may or may not, and usually is not at the beginning stages, be
manifested in enlarged tissues.
Hyperplasia or hypertrophy of the oral tissue may vary in degree
from a slight increase in tissue bulk to definitely disfiguring
enlargement, and may be grouped into three classes: (1) small
enlargement associated with some local irritations on tissues
predisposed to fibrous poliferetion, (2) idiopathic fibrous
hyperplasia, and (3) those caused by local application or systemic
intake of drugs and other chemical agents, such as
diphenylhydantoin.
CAUSES OF ORAL TISSUE ENLARGEMENT
A. local inflammatory, irritating and traumatic factors
1. poor oral hygiene, accumulations of calculus
2. Malposed teeth, faulty contact points
3. Unusual toothbrush habits
4. Occlusal overfunction
5. Irritation from ill-fitting crowns, clasps, prosthetic or
orthodontic appliances
6. Mouthbreathing
B. systemic predisposing factors
1. endoctrine
a. Puberty
b. Menstration and pregnancy
c. Hypothyroidism and pituitary disfunction
d. Diabetes
e. Gonadal disturbances
2. Nutritional
a. Scurvy
b. Subclinical nutritional deficiencies of mixed types, including B
complex
3. Blood dyscrasias
a. The Leukemias -- particularly monocytic and myelogenous
b. Polycythemia vera
c. Cooley's amenia
4 Drugs
a. Diphenylhydantoin (Dilantin) sodium
b. Barbituates
5. Idiopathic forms
a. Diffuse fibromatosis of the gums
C. post extraction swelling
hypertrophic or hyperplastic oral tissue may be confined to one
part of the mouth, such as in the case of post extraction swelling,
or it may extend over the entire oral tissue; it may be confined to
the gingival margin or enlarge to the extent of the entire oral
cavity tissue from the gingiva to the buccal and lingual
reflections and to the tonsilar and pharyngeal areas. The initial
clinical picture usually exhibits and etiological factor of
congestion with edema and hyperemia followed by less of the
inflammatory character and thickening and fibrosis of the
connective tissue layer if the causes of oral tissue enlargement
are allowed to persist.
Many theories have been postulated for the treatment of hyperplasia
and hypertrophy of the oral tissue; treatment ranging from the use
of diuretics, steroids, anti-inflammatory agents, and other
biochemicals with questionable results. The treatment of choice
accepted by most clinicians knowledgeable in the art of
periodontology is gingivectomy (surgical excission of the
hypertrophied or hyperplastic tissue) if the condition is not too
severe and complete clearance of teeth (full mouth extraction) if
the enlarged tissue interferes with patient's mastication.
Heretofore there is no known therapeutic treatment for the cure or
control of hyperplasia or hypertrophy, whether associated with
diphenylhydantoin sodium or other irritating causative factors, and
surgical excission of the enlarged tissue around the teeth is about
the only reliable treatment; however, recurrence of hyperplasia or
hypertrophy of the oral tissue is certain to reappear after a few
months. Complete clearance of the teeth is necessary if the
condition is severe. This invention relates to a process and
composition for treatment of the enlarged oral tissue which has not
been suggested before and is novel in its pharmacodynamic action on
the enlarged tissue.
The mode of diphenylhydantoin sodium action on the enlarged tissue
is diversified and complicated and certain cytologic actions are
not clearly elucidated. However, the resultant enlargement of the
oral tissue due to this drug is similar clinically to the
enlargement caused by other chemical and physical irritants. For
this obvious reason the pharmodynamic action of the drug
diphenylhydantoin on the oral tissue is emphasized in this patent
application but in no way it should restrict the use of this
invention only to the enlargement caused by this drug.
Many studies have been made in regard to the causal relationship of
diphenylhydantoin sodium with oral tissue hyperplasia or
hypertrophy and the resultant fibrosis of the said tissues with all
investigators agreeing that diphenylhydantoin hyperplasia is
essentially the result of irritation of the gingival tissue around
the teeth by the drug when taken systemically. Hyperplasia or
hypertrophy does not occur in the edentulous areas which indicates
that the teeth serve as nodi of diphenylhydantoin sodium
irritation. Almost all investigators agree that there is no
relationship between the amount of diphenylhydantoin intake and the
degree of resultant fibrous hyperplasia. Perhaps this fact
indicates that the action of diphenylhydantoin on the tissues works
on the "all or none" principle -- even a small amount of
diphenylhydantoin will exert the same irritating effect on the
tissues or it will not effect the tissues at all. Therefore, some
metabolic changes occur at the tissue level that prevents
reabsorption of the diphenylhydantoin by the venous circulation and
consequent elimination by the kidneys in the urine, making possible
the retention of the diphenylhydantoin sodium complex in the
intercellular substance to initiate fibrosis. Hypertrophy and
hyperplasia of the oral tissues continues to attract interest in
the dental profession especially in periodontology, because of the
lack of treatment for this condition and the high percent of
occurrence in patients under treatment with diphenylhydantoin for
the control of convulsive seizures. The overwhelming gingival oral
tissue reaction to this drug necessitates more and more effect on
the dental profession to treat this condition as a serious one
since heretofore there are no biochemicals available to aleviate
this condition thereapeutically; only surgical intervention or
taking the drug away from the patient; will provide temporary
relief. Complete removal of the teeth will usually result in total
elimination of this problem.
Local or systemic irritation, be it chemical such as
diphenylhydantoin sodium or physical such as faulty dental
restorations and prosthesis, will initially start in edema and
gradually progress to fibrosis unless there is some sort of
thereapeutic intervention between the two points to prevent the
extreme -- fibrosis. Edema can, and usually does, precede
hypertrophy and hyperplasia and finally fibrosis, but it is not a
part of the fibrous process itself, edema being a condition
characterized with unusual accumulation of extravascular fluid in
the tissues. The causative factor in production of edema is the
apparent imbalance between the transudation of fluid from the
circulation and its return by the vascular system. Exchange of
water and solutes across the capillary membrane occurs by
filtration at the artetiolar end of the capillary bed and reverse
flow, or absorption, at the venous end. The two most important
factors that influence the rate of fluid and solutes across the
capillary membrane are tissue tension and capillary
permeability.
Diphenylhydantoin sodium was introduced into medicine for
symptomatic treatment of epileptic seizures and has become the drug
of choice for treatment and control of convulsive conditions due to
its non hypnotic effect on the central nervous system. The primary
concern of the dental profession to this drug is the effect it has
on the oral gingival tissue causing fibrous proliferation which
results in fibrous enlargement of the gums. Gingiva is that portion
of the oral mucous membrane which surrounds the teeth and is not
attached to the underlying alveolar bone. It differs from the
mucous membrane in that the epithelium is thicker and hornified to
better resist the constant stresses applied to the tissue during
mastication. Once the teeth are removed the gingiva ceases to
exist; then it becomes attached to the alveolar bone and the
epithelium looses its hornification. Some periodontists hold the
gingiva to be different tissue from mucous membrane and this
differentiation is particularly true in case of fibrous hyperplasia
due to dilantin since the drug affects only the gingiva, the tissue
around the teeth, and has no effect on the rest of the mucous
membrane of the mouth.
Diphenylhydantoin sodium when taken orally, in either flavored or
oil vehicle, is partially dissolved in the intestine and readily
absorbed by the circulation and carried throughout the body,
especially in the areas demonstrating high metabolic rate of the
tissues such as brain, the hair follicle, the oral gingiva etc.
Since the alkalinity of the gastric fluid and of the oral tissues
is not high enough to provide complete dissolution of
diphenylhydantoin sodium (the pH must be about 11.7 to obtain
saturated solution) the unchanged drug, due to its affinity for the
tissues in high metabolic rate, finds its way into the
extracellular ground substance of the oral gingiva. Once in the
ground substance of the gingiva diphenylhydantoin conjugates with
glucuronic acid -- a metabolite of hyaluronic acid, and in this
form it is excreted in the urine. The metabolites found in the
urine are conjugated with glucuronic acid. The conjugation reaction
involves combination of a metabolite of diphenylhyantoin with some
other substance, such as the metabolite of hyaluronic acid -
glucuronic acid, followed by the elimination of the resulting
conjugate. The dissolved diphenylhydantoin in the ground substance
of the oral gingiva is easily dissociated even by weak acids such
as carbon dioxide (CO.sub.2), which is the biproduct of metabolism
in the tissues whenever the tissues are active in response to a
chemical or physical stimulant, with the regeneration of
5,5-diphenylhydantoin. The metabolities of diphenylhydantoin,
hydantoic acid and amino acid, by the action of carbon dioxide and
the subsequent increase of carbonic acid (H.sub.2 CO.sub.3) are
regenerated to the 5,5-diphenylhydantoin which is made available
for more conjugation with glucuronic acid and therefore binding in
the ground substance of the gingiva. This complex, unless
eliminated by the urine, will prolong the irritation of the
fibroblasts resulting in secretion of collagen for formation of
fibrous tissue bundles. It now becomes apparent that
diphenylhydantoin in the oral tissues undergoes a vicous cycle of
disassociation and regeneration.
Another important characteristic of diphenylhydantoin action in the
gingival tissue is that it stimulates liberation of histamine and
histamine-like substances and reduces the amount of serotonin.
Histamine is found in the cells of most connective tissue and its
primary function upon liberation is to vasodialate the arterioles
and capillaries thereby bringing more circulation to the injured
area and to lower the capillary permeability. Diphenylhydantoin in
regard to the capillary membrane has dual effect; initially it
stimulates the chemoreseptors of the endothelical cells to secrete
histamine and secondly it acts directly on the smooth muscle of the
arteries and arterioles causing lowering of membrane permeability.
Diphenylhydantoin and histamine both jointly vasodialate the
capillaries and increase the capillary membrane permeability
allowing diffusion of not only crystalloids but also colloidal
substances from the vascular system and into the tissue spaces.
This particular action of diphenylhydantoin, vasodilation and
alteration of capillary membrane permeability, is essentially the
reason why edema is preceding or superimposed condition to fibrosis
of the gingiva in diphenylhydantoin therapy.
The outer layer of the mucous membrane -- the hornified epithelium,
is acidophil in character and the underlying submucous layer is
alkaline having pH of approximately 7.4. The alkalinity of the
submucous layer, where the ground substances are found, maintains
the consistency of the hyaluronic acid gel-like and stable.
Alkalinity having pH (or more precisely pOH) of 7.4 is not high
enough to keep the diphenylhydantoin sodium present in the tissues
in solution but is high enough to prevent disaggregation of
hyaluronic acid by the carbonic acid which is produced during
tissue metabolism. The viscous consistency of the ground substance
keeps the conjugate of the diphenylhydantoin - glucuronic acid
bound or captured within the tissue spaces preventing the
conjugated complex from being absorbed and subsequently excreted by
the venous circulation. Retention of the diphenylhydantoin complex
in the ground substance enables the drug to prolong and intensify
its stimulatory effect on the fibroblasts resulting in gingival
fibrosis.
SUMMARY OF THE INVENTION
This invention pertains to compositions uniquely suited for the
treatment of hypertrophied or hyperplastic tissue and the pain
associated therewith and which comprise in combination a
vasoconstricting alkaloid, an antihistamine, and an anesthetic. The
preferred alkaloids for use in this invention are aromatic amines
having between about 6 to 10 carbon atoms and aliphatic amines
having between about 4 to 7 carbon atoms. The preferred
antihistaminics are those of the skeletal structural formula:
##SPC1##
wherein X may be oxygen, nitrogen or carbon, and R, R' and R" are
either aryl, alkyl or aralkyl groups.
The antihistamine should have a minimum molecular weight of about
150, and each of the aryl, alkyl or aralkyl groups should contain
in the range of about 2 to 16 carbon atoms. If X in the structure
shown above is nitrogen, the resulting compound may be viewed as an
ethyleadiamine derivative; if oxygen, as an aminoalkyl ether; and
if carbon as an alkylamine. Attached through the carbon, oxygen or
nitrogen is the so-called nucleus of the antihistaminic drug.
Preferably, this nucleus should consist of a minimum of two aryl or
aralkyl groups.
The anesthetics preferred for use in this invention are the amino
esters of aromatic acids and aminoacyl amides of aromatic acids.
Such compounds will generally contain a maximum of about 26 carbon
atoms.
The compositions of this invention should contain the
vasoconstricting alkaloidal and antihistaminic each in an amount of
about 0.0125 to 5.0 percent by weight based on the weight of the
entire composition. When the alkaloid is present in an amount in
excess of about 1.0 weight percent then the weight ratio of
alkaloid to antihistamine is preferably about 1:05, that is, the
amount of antihistamine employed is about half that of the
alkaloid. When the concentration of alkaloid is less than about 1.0
percent, then good results have been found using an equal amount of
the antihistamine, or an alkaloid to antihistamine ratio of 1:1.
These ratios are not absolute and are being set forth only as a
guide.
The amount of anesthetic compound employed is, of course, very
dependent on the compound selected. For example, tetracaine
hydrochloride because of its rapid absorption by the blood and
relative toxic reaction when ingested in large amounts, should be
used in minimal amounts. Good results have been achieved in the
treatment of pain associated with hyperplasia or hypertrophy with
concentrations in the range of about 0.0125 to 5.0 weight percent.
On the other hand, benzocaine is relatively free of any side
effects and toxic reactions, even when used in high concentrations,
and has been used successfully at concentrations in the range of
0.0125 to 20.0 weight percent. Accordingly, the anesthetic compound
should be present in an amount of about 0.0125 to 20.0 weight
percent based on the weight of the entire composition.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Application of the composition of this invention to the oral
tissues, for example, either in mouthwash or toothpaste
formulations, will readily penetrate the outer keratinous
epithelial layer, break the electrical polarization that exists
between the acidic epithelium and the alkaline submucosa and
diffuse into the deeper submucous tissues. Brushing or massaging of
the gums will express the air bubbles from the epithelium,
particularly the air bubbles in the ducts of the secretory glands
which extend deep into the submucosa, providing entrance and
facilitate absorption of the drug. Once the composition gains
entrance in the ground substance of the enlarged tissue its
alkalinity will readily neutralize the acid present during the
tissue activity resulting in metabolic alkalosis. This
neutralization tends to increase the pH of the tissue fluid from
7.4 to about 10-12, depending on the dissociation of the alkaline
composition to free hydroxyl group and the amount of carbonic acid
present in the tissues for neutralization. Increased alkalinity of
the tissue fluid, especially around pH 11-12, results in increased
dissolution of diphenylhydantoin either in the conjugated or
metabolic form, thusly eliminating the drug by the venous capillary
system. The change of tissue acidity affects the hydrolysis of
ground substance -- hyaluronic acid. On hydrolysis, hyaluronic acid
yields equimolar amounts of d-glucoseamine, d-glucuronic acid, and
acidic acid and is believed to contain a repeating disaccharide
unit comprising N-acetyl glucoseamine glucuronide. Hydrolysis of
the glucuronic acid decreases the viscosity of the ground substance
freeing the diphenylhydantoin portion from the
diphenylhydantoin-glucuronic acid conjugate to be dissolved by the
alkaline composition, particularly when the pH is 11-12, and
subsequently eliminated by the kidneys. The dissolution of the drug
diphenylhydantoin in the tissue fluid will result in decrease of
stimulatory effect the drug has on the fibroblasts therefore
lessening the chance for fibrosis.
Another important function of this invention, in acid as well as
alkaline formulations, is the effect it has on the collagen
material of the oral tissues. Collagen is the most abundant protein
material in any connective tissue. The fibrous connective tissue
contains 63 percent water, and 31.6 percent collagen with small
amount of elastin and mucoids. Collagen is a tough, inert,
insoluble in water fiber but slowly converted to gellatin by
boiling water, dilute acids and alkalies. Diphenylhydantoin, being
an irritant, stimulates the fibroblasts to secrete collagenous
material which is precipitated outside the cells forming
interconnected bundles of the insoluble threads. This process of
fiber formation is called fibrosis. The acid or alkaline character
of my composition will retard the excretion of the collagen
material by the fibroblasts (fibroblasts are germinating cells, or
precursors, giving rise to new fibers) thusly minimizing, if not
completely eliminating the possibility of fibrosis. The acidity, or
the alkalinity, of the composition of this invention will gradually
convert the newly formed collafenous fiber into more easily
reactive gelatin which is readily digestable by tissue enzymes and
removed by the circulation. The composition of this invention will
further gradually break the bonds linking parallel polypeptide
chains to single peptide chains of gelatin. The compensatory
alkalinity of the tissue fluid during the treatment with the
compositions of this invention is opposed by the buffering system
of the intercellular fluid and the excess alkalinity will be
neutralized by the carbonic acid of the tissue fluid in order to
keep the proper bicarbonate/carbonic acid ratio 20:1 at pH 7.4.
The vasoconstrictor component of the compositions of this
invention, such as the sympathomimetic amine phenylephrine
hydrochloride, upon entrance into the ground substance of the
tissue acts directly on the chemoreseptors of the endothelical
cells of the capillary membrane. It causes swelling of the cells
thereby decreasing the lumen of the capillaries and restoring the
patency of the membrane. This vasoconstriction of the arterioles
and capillaries (the venuoles are not affected to an appreciable
degree) stops the escape, or leakage, of the larger molecules of
proteins and the unchanged diphenylhydantoin sodium from the
circulation and into the tissues thereby restoring the normal
balance of vascular and extravascular fluid and electrolytes
exchange. The prevention of diphenylhydantoin escape into the
tissues and the subsequent elimination of the metabolites of
diphenylhydantoin from the tissues by the venous circulation,
reduces the amount of the drug available for stimulation of the
fibroblasts to secrete collagenous material and form the insoluble
fibers. Decrease of diphenylhydantoin metabolites from the tissues
liberates the calcium ions from the complex
diphenylhydantoin-calcium conjugate allowing it to return to the
cement material of the endothelial cells of the capillary membrane
and active cells. The vasoconstriction of the capillaries deprives
the hypertrophied or hyperplastic cells from nutrition and
subsequent decrease either in the size of the cells themselves or
the number of cells. In hypertrophy or hyperplasia, especially at
the initial stages, there is increase in the number of capillaries
which is evident under microscopic examination. The
vasoconstrictor, for example, phenylephrine hydrochloride, by
virtue of its action on the endothelial cells of the capillary
membrane decreases and sometimes virtually eliminates, particularly
the newly formed capillaries, from being able to supply the
hypertrophied or hyperplastic cells with nutritious materials
therefore practically "starving" the new cells to death. This event
is especially true before fibrosis is allowed to proceed.
The antihistamine, as for example, antazoline hydrochloride, upon
entrance into the ground substance of the oral tissues prevents the
access of histamine liberated by the excitatory effect of
diphenylhydantoin on the tissue cells, to its receptor site in the
endothelial cells of the capillary membrane and thereby blocks the
response of the effector cell to the amine. The antihistamine
possesses no pharmacodynamic action; it does not react to have
antagonistic action with the histamine. The antihistamine occupies
the receptor site of the endothelial cells without causing a
cellular response. This characteristic of the antihistamine used in
my formulations potentiates the physiological antagonism of the
sympathomimetic amine to the effects of the histamine on the
capillary membrane resulting in more profound vasoconstriction. The
pharmacodynamic action of, for example the phenylephrine
hydrochloride - antazoline hydrochloride combination is more
intense than that produced by either agent used alone.
Phenylephrine hydrochloride gives a very rapid onset of reduction
of local oral tissue swelling while antazoline hydrochloride
prolongs the reduction in the size of the oral tissue by its direct
action on the capillary membrane.
The most beneficial advantage of vasoconstrictor-antihistamine
combination is virtually elimination of any side effects produced
by either agent used alone. The sedative effect of the
antihistamine will counteract the stimulant effect of the
sympathomimetic agent.
In obtaining the new and novel treatment, this invention makes use
of certain alkaloid compounds or substances which are
sympathomimetic amines, and which possess among other properties
those of serving as decongestants or vasoconstrictors effecting
shrinkage of the overgrown oral tissues. Preferred are aromatic
amines having been 6 to 10 carbon atoms, and aliphatic amines
having a total of between 4 to 7 carbon atoms. Some examples of
useful compounds are: ##SPC2##
Ephedrine sulfate, phenylephrine hydrochloride, cyclopentamine
hydrochloride, methylhexaneamine hydrochloride, and oxymetazolin
hydrochloride, are the preferred sympathomimetics because they can
be employed in aqueous, oil and alcohol solutions and in mixtures
thereof. They are readily available, relatively stable, do not
decompose readily to light, heat or air. They can be boiled for
sterilization, have a long duration of action and are substantially
free of aftercongestion.
The antihistamine employed in the compositions of this invention
may be any of the commercially available compounds, the majority of
which have the structural formula: ##SPC3##
in which it is apparent that core of the structure is a substituted
ethylamine, which is also present in histamine. It is most likely
that it is this portion of the molecule which competes with
histamine for cell receptors. In most instances, the ethylamine
grouping is present as a straight chain, but in a few it is part of
a ring structure.
Nearly always, the substituted ethylamine of histamine antagonists
is teritary, with the activity of secondary or primary amines being
greatly attenuated. Furthermore, optimal substituent groups on the
amine in most senses is N-dimethylalkyl. Generally N-diethyl
compounds are less active and more toxic. Occasionally, the
substituted amine is incorporated in a heterocyclic ring without
loss of activity. Quarternization of the tertiary amine diminishes
but does not abolish activity.
As noted earlier in this application, X in the structure may be
oxygen, nitrogen or carbon and it is not possible to make any great
distinction between these with respect to antihistaminic activity.
In addition, the following can be associated with antihistaminic
activity; aminoketones, secondary aminoalcohols, alkylesters and
haloalkylamines.
Attached through the carbon, oxygen or nitrogen is the socalled
nucleus of the antihistamine which should consist of a minimum of
two aryl or aralkyl groups or their equivalent in a polycyclic ring
system, with the nucleus having a minimum molecular weight of
150.
Some of the typical antihistaminics are the hydrochlorides,
citrates, maleates and succinates such as:
antazoline hydrochloride C.sub.17 H.sub.19 N.sub.3.sup.. HCL
tripelennamine hydrochloride C.sub.16 H.sub.21 N.sub.3.sup.. HCL
tripelennamine citrate C.sub.16 H.sub.21 N.sub.3.sup.. (C.sub.6
H.sub.5 O.sub.7)2 thonzylamine hydrochloride C.sub.16 H.sub.23
CLN.sub.4 O.sup.. HCL methapyriline hydrochloride C.sub.14 H.sub.19
N.sub.3 S.sup.. HCL methapheniline hydrochloride C.sub.15 H.sub.20
N.sub.2 S.sup.. HCL pyrilamine maleate C.sub.17 H.sub.23 N.sub.3
O.sup.. C.sub.4 H.sub.2 O.sub.3 chlorphenamine maleate C.sub.16
H.sub.19 CLN.sub.2.sup.. C.sub.4 H.sub.2 O.sub.3 chlorothen
C.sub.14 H.sub.18 CLN.sub.3 S pheniramine C.sub.16 H.sub.20 N.sub.2
pheniramine maleate C.sub.16 H.sub.20 N.sub.2.sup.. C.sub.4 H.sub.2
O.sub.3 chlorcyclizine hydrochloride C.sub.18 H.sub.21
CLN.sub.2.sup.. HOL diphenhydramine hydrochloride C.sub.17 H.sub.21
NO.sup.. HCL doxylamine succinate C.sub.21 H.sub.28 N.sub.2 O.sub.5
phenyltoloxamine citrate C.sub.17 H.sub.21 NO diphenylpyraline
hydrochloride C.sub.19 H.sub.23 NO.sup.. HCL phenindamine tartrate
C.sub.19 H.sub.19 N thenyldiamine hydrochloride C.sub.14 H.sub.19
N.sub.3 S
Antazoline hydrochloride, diphenhydramine hydrochloride
thonzylamine hydrochloride, and chlorphenamine maleate are the
preferred antihistaminics in this invention due to their lack of
incidence of side action and low tissue irritancy; however, any of
the above named antihistaminics may be used in this invention
without lowering the potency and the effectiveness of the fluid and
toothpaste compositions.
As indicated above, this invention is concerned with reducing the
size of enlarged oral tissue and alleviation of pain associated
with hyperplasia. The reduction in size of the tissue is effected
by the action of the sympathiomimetic amine directly on the
chemoreseptors of the endothelial cells of the capillary membrane
causing vasoconstriction of the capillaries and arterioles, and by
the competitive inhibition of the antihistaminic drug on the
histamine by occupying the receptor site of the endothelial cells
without causing cellular response. The pain is alleviated by the
action of the anesthetic or the analgesic on the nerve endings of
the enlarged tissue.
The anesthetic employed must be capable of blocking nerve
conduction when applied locally to nerve tissue and should not be
irritating and must produce anesthesia without causing damage to
nerve structure.
Generally, topical anesthethics are weak organic bases which are
poorly soluble in water. However, these bases will react with
acids, particularly hydrochloric acid, to form water soluble salts
which are suitable for topical application. There is abundant
evidence to show that the neutralization of the acid salt and the
liberation of the free base are essential for anesthetic
activity.
Little is known regarding the pharmacodynamics of the topical
anesthetics. The drug appears to have a selected affinity for
voluntary muscle nerves, proprioseptors, cold and hot, and pressure
nerves, etc. The anesthetic apparently passes through the
neurilemma and into the axon where it combines with the nerve fiber
chemically, altering its function of conductivity. The topical
anesthetic will also affect the synaptic transmission of nerve
impulses possibly by affecting the metabolism of acetylcholine or
competing with it in an enzyme system. The topical anesthetics are
fat-soluble and to make the alkaloids water soluble they are
dispensed as acid salts.
Upon application of the composition of this invention on the oral
tissue, the anesthetic salt undergoes three separate but
interdependent stages: (1) neutralization, (2) hydrolysis, and (3)
resynthesis. NEUTRALIZATION:
The neutralization of the anesthetic salt, which is strongly acid
in reaction, is affected by the sodium bicarbonate (NaHCO.sub.3)
present in the tissue. The anesthetic salt is hydrophilic in nature
and reacts with the sodium bicarbonate from the tissue raising the
pH of the environment to over 7.5. The reaction may be represented
as follows: ##SPC4##
or as in case of Benzocaine ##SPC5##
The ability of the undissociated free base to penetrate cellular
membranes is the first requisite for anesthetic activity. Once the
neutralization is satisfied the anesthetic is further dissociated
to cationic form which reacts readily with the intracellular
constituents of the nerve fiber, principally the lipids. This
ionization reaction may be represented as
RN + HOH.fwdarw.RNH.sup.+ + OH.sup.-
where now the free base is in form of cations and has the tendency
to escape from solution into the state of absorption on cellular
constituents. Once the equilibrium of the neutralization reaction
is reached, the free anesthetic base becomes hydrophobic and
lipophilic to form a temporary lebile union with the axoplasm. This
complex temporary lebile structure interferes with breakdown of
acetylchloline by the enzyme cholinesterase. Acetylcholine is a
chemical mediator present in the nerve tissue as a non diffusable,
physiologically inactive form and not susceptible to hydrolysis. In
this form it is referred to as a procursor or bound acetylcholine
which is found in the individual nerve fibers and at the synapse.
Upon stimulation of a nerve to conduct an impulse, acetylcholine is
liberated by each individual cell of the nerve fiber to conduct and
transmit an impulse from one cell to another all along the axon and
across the myoneural junction to the muscle affected by that
particular nerve causing excitation. To prevent continuous and
rapid firing of stimuli along the axon, acetylcholine is almost
immediately destroyed by the enzyme acetylcholine esterase, or
simply cholinesterase. This complex biochemical reaction may be
represented ##SPC6##
This reaction is reversable under normal tissue conditions so that
subsequent to the stimulation of the nerve fiber, resynthesis of
the end products (choline and acetic acid) to the original
substance (acetylcholine) occurs in the presence of enzyme choline
acetylase and coenzyme acetase.
The free base, which has now penetrated the neurilemma, reacts
directly with potassium and magesium ions in the axoplasm
preventing the resynthetization of acetylcholine by denying enzyme
choline acetylase its activators. The potassium and magnesium ions
are necessary to be present in the substrate for the enzyme choline
acetylase to be effective. They are referred to as activators. The
enzyme choline acetylase catalyses the transfer of acetyl radical
from CoA-acetate to choline which is essential for synthesis of
acetylcholine. The free anesthetic base in effect acts as an
anti-cholinesterase by the nature of its interference with
cholinesterase in breaking down of acetylcholine resulting in
prolonged parasympathetic activity. The anesthetic effect will last
as long as the union of the free base and the lipid constituents of
the axoplasm is left intact or until the enzymatic accumulation in
the nerve tissue, the substrate, is concentrated enough to reverse
the reaction and change the direction of the equilibrium to the
side of the hydrolysis of the drug.
Hydrolysis:
following the absorption, benzocaine and tetracaine are hydrolysed
to ethanol and para-aminobenzoic acid and dimethylaminoethanol and
para-amino benzoic acid respectively by the enzyme esterase. The
hydrolysis reaction within the nerve axoplasm of benzocaine
hydrocloride may be represented as ##SPC7##
and the hydrolysis of tetracaine hydrochloride may be represented
as ##SPC8##
The biproducts ethanol and para-amino benzoic acid and
dimethylaminoethanol and para-amino benzoic acid of benzocaine and
tetracaine respectively, are inert compounds and are removed from
the tissue by routine channels of elimination. Eighty percent of
para-amino benzoic acid is excreeted in the urine and only 30
percent of ethanol and dimethylaminoethanol is recovered in the
urine. The low percentage of the recovered alcohols is due to some
being changed to aldehyde or ketone by the nerve cell protein and
as such carbohydrates are used by the nerve as a source of energy
during transmission of an impulse. The respiratory quotient of a
metabolizing nerve is very close to 1.0 which suggests that the
nerve is utilizing carbohydrates almost exclusively.
The unhydrolysed benzocaine and tetracaine which enter the blood
circulation are rapidly detoxified chiefly by the liver and
excreted in the urine by the kidneys.
Resynthesis
this phase deals primarily with resynthesis of the enzyme
acethylcholine and the return of the nerve constituents to their
normal biochemical equilibrium. Clinically, this is the so-called
wearing-off period; chemically, it may be represented as
##SPC9##
The rate at which the lipids of a nerve tissue are exchanged are
relatively slow in comparasion to that of an active organ such as
the liver. Tracer studies with deutorium indicate that while 50
percent of the liver fats may be exchanged in 24 hours, only 20
percent of the fat in nerve tissue is replaced in 7 days. This
explains the slow hydrolysis of the anesthetic solution in the
nerve tissue and its rapid destruction in the liver.
Instillation of the composition of this invention in either fluid,
paste, or tablet form on the oral tissue will have three distinct
and yet coordinated functions. (1) the action of the
sympathomimetic amine on the endothelial cells of the capillary
membrane resulting in vasoconstriction of the said capillary
membrane, (2) the action of the antihistaminic on the histamine in
the tissues potentiating the effect of the sympathomimetic amine,
and (3) the action of the analgesic agent on the nerve fibers of
the affcted hyperplastic or hypertrophied and enlarged oral tissue
resulting in blockage of the sensory pain impulses and temporary
anesthesia. In addition, the vasoconstriction caused by the
sympathomimetic amine will prolong the effect of the topical
anesthetic due to the resultant decrease in the absorption of the
anesthetic drug. This decrease in the absorption of the anesthetic
drug is significant since it will require less amount of the
anesthetic to obtain the necessary degree of analgesia, decreases
the possibility of toxicity, and prolongs the duration of the
analgesia.
The topical anesthetics, which are analgesic, used in this
invention are generally secondary or tertiary amino esters of
aromatic acids, or secondary or tertiary aminoacyl amides of
aromatic acids, the ester type having the benzoic acid, parabenzoic
acid or meta-benzoic acid as the nucleus of the structure with
aromatic or aliphatic substutions of up to 14 carbons atoms each,
and the amide type having the xylene or toluene radical as the
nucleus of the structures with, again, aromatic or aliphatic
substitutions of up to 14 carbons each. The ester type has the
general structural formula: ##SPC10##
where R.sub.1 with its carboxyl group may be benzoic acid,
para-amino benzoic acid, or meta-amino benzoic acid and R.sub.2,
R.sub.3 and R.sub.4 are aromatic or aliphatic radicals of up to 14
carbon atoms each.
The amide type has the general structural formula ##SPC11##
where R.sub.1 is either xylene or toluene substituted and R.sub.2,
R.sub.3 and R.sub.4 are aromatic or aliphatic radicals of up to 14
carbon atoms.
Some of the typical local and topical anesthetics employed today
are the synthetic products such as
cocaine hydrochloride C.sub.17 H.sub.21 NO.sub.4.sup.. HCL procaine
hydrochloride C.sub.13 H.sub.20 N.sub.2 O.sub.2.sup.. HCL lidocaine
hydrochloride C.sub.14 H.sub.22 N.sub.2 O.sup.. HCL mepivacaine
hydrochloride (Carbocaine hydrochloride) C.sub.15 H.sub.22 N.sub.9
O.sup.. HCL prilocaine hydrochloride (Citanest hydrochloride)
C.sub.13 H.sub.19 N.sub.2 O.sup.. HCL pyrrocaine hydrochloride
C.sub.14 H.sub.20 N.sub.2.sup.. HCL butethamine hydrochloride
(Monocaine hydrochloride) C.sub.13 H.sub.20 N.sub.2 O.sub.2.sup..
HCL metabutethamine hydrochloride (Unicaine hydrochloride) C.sub.13
H.sub.20 N.sub.2 O.sub.2.sup.. HCL isobucaine hydrochloride
C.sub.15 H.sub.23 N.sub.2 O.sup.. HCL tetracaine hydrochloride
(Pontocaine hydrochloride) C.sub.15 H.sub.24 N.sub.2 O.sub.2.sup..
HCL propoxycaine hydrochloride (Ravocaine hydrochloride) C.sub.16
H.sub.26 N.sub.2 O.sub.3.sup.. HCL benzocaine C.sub.9 H.sub.11
N.sub.2 O butacaine sulfate (Butyn Sulfate) C.sub.18 H.sub.30
N.sub.2 O.sub.2.sup.. H.sub.2 SO.sub.2 dyclonine hydrochloride
(Dyclone hydrochloride) C.sub.18 H.sub.27 NO.sub.2.sup.. HCL
dibucaine hydrochloride (Nupercaine hydrochloride) C.sub.20
H.sub.29 N.sub.3 O.sub.2.sup.. CHL piperocaine hydrochloride
(Neothesin hydrochloride) C.sub.16 H.sub.23 NO.sub.2.sup.. HCL
phenacaine hydrochloride (Holocaine hydrochloride) C.sub.18
H.sub.22 N.sub.2 O.sub.2.sup.. HCL.sup.. H.sub.2 O diperodon
hydrochloride (Diothane hydrochloride) C.sub.22 H.sub.27 N.sub.3
O.sub.4.sup.. HCL dimethisoquin (Prulargan, Quinisocaine, Quotane,
Prulargin) C.sub.17 H.sub.24 N.sub.2 O naepane (Naepaine, Amylsine)
C.sub.14 H.sub.22 N.sub.2 O.sub.2
The combination of Benzocaine and Tetracaine hydrochloride was
found to be most effective in producing topical anesthesia due to
Tetracaine's high activity even in very low concentrations and its
rapid onset of anesthesia and Benzocaine's low solubility. There is
a group of local or topical anesthetics characterized by the fact
that its members are poorly soluble in water, and Benzocaine is one
of them. Due to its insolubility, the compounds are not absorbed
with sufficient rapidity to be toxic and therefore can be applied
directly to the wounds and open surfaces on the mucous membrane.
For the same reason they remain localized at the site of
application for long periods of time, which accounts for their
sustained anesthetic action. In my formulations Tetracaine will
produce a very rapid onset of anesthetic action even in
concentrations of less than 1.0 percent without any toxic effects
and Benzocaine will give a sustained anesthetic effect. The
vasoconstrictor phenylephrine hydrochloride adds to the sustained
actions of both topical anesthetic agents by prolonging the
absorption of the drugs by the circulation.
Any one, or any combinations, of the above named topical
anesthetics may be used in lieu of Benzocaine and Tetracaine to
produce topical analgesia without departing from the intent and the
scope of the invention; however, the solubility, toxicity, potency,
and activity of each individual drug must be considered in the
selection of the topical anesthetic.
Some other compounds that may be employed as topical anesthetics
are some aromatic alcohols such as Benzyl Alcohol and Saligenin;
quinine salts such as Quinine and Urea Hydrochloride;
chlorobutanol; ethyl chloride; phenolic compounds such as
amyltricresol, parachlorophenol, cresol, creosote, eugenol,
guaiacol, phenol, thymol and other related organic compounds.
The compositions of this invention may be fluid, paste, spray or
tablet preparations of the vasoconstrictor-antihistamine-analgesic
combination. The following examples illustrate such
preparations.
EXAMPLE I
Each cc of a fluid composition contains:
phenylephrine hydrochloride U.S.P. 10.00 mg 1.00 % diphenhydramine
hydrochloride U.S.P. 5.00 mg 0.5 % benzocaine hydrochloride 50.00
mg 5.00 % tetracaine hydrochloride 10.00 mg 1.00 % benzalkonium
chloride 2.00 mg 0.2 % saccharine sodium 0.18 mg 0.018 % spearmint
oil 0.15 mg 0.015 % sodium chloride 3.90 mg 0.39 % sodium
thiosulfate 0.20 mg 0.02 % alcohol 80.00 mg 0.8 % distilled water
q.s. 1 cc
This composition is intended to be used as a mouthwash, rinse, or
gargle. The patients are instructed to swish about one to one half
fluid ounce of the solution in the mouth for approximately 1 to 2
minutes and expel the remainder. Rinsing with water after usage is
discouraged for at least 1 hour for the obvious reason of better
absorption of the drug. The procedure should be repeated two to
four times daily, depending on the severity of the condition, or as
recommended by the physician or dentist.
EXAMPLE II
Each cc of a spray composition contains:
phenylephrine hydrochloride 10.00 mg 1.00 % diphenhydramine
hydrochloride 5.00 mg 0.5 % benzocaine hydrochloride 10.00 mg 1.00
% tetracaine hydrochloride 5.00 mg 0.5 % zirconium oxide 10.00 mg
1.00 % menthol 0.09 mg 0.009 % camphor 0.98 mg 0.098 % calamine
9.80 mg 0.98 % isopropyl alcohol 95.00 mg 9.5 % methylparaben 0.80
mg 0.08 % propylparaben 0.20 mg 0.02 % propellants 873.33 mg 87.33
%
This cool, soothing, composition is intended to be used as a spray.
The patients are instructed to spray the affected area
approximately six times (1 cc) with the solution and are
discouraged to rinse with water for approximately 1 hour after
usage. The procedure should be repeated two to four times daily,
depending on the severity of the condition, or as recommended by
the physician or dentist.
EXAMPLE III
Each tablet or cone of the composition contains:
phenylephrine hydrochloride 50.00 mg 1.00 % diphenhydramine
hydrochloride 25.00 mg 0.5 % benzocaine hydrochloride 750.00 mg
15.00 % tetracaine hydrochloride 20.00 mg 0.4 % sodium chloride
19.50 mg 0.39 % glucose 1.00 mg 0.02 % polyethylene glycol 6000
3000.00 mg dl-leucine q.s. 5 Gm
This water soluble tablet or cone composition is intended to be
used as an insert or a packaging of the affected areas. In post
extraction and post surgical cases the patient is instructed to
insert the tablet or the cone into the tooth socket or the
incission for the effective treatment of hypertrophy or hyperplasia
and tissue enlargement and the associated pain. The procedure
should be repeated four times daily or as required for pain.
EXAMPLE IV
Each one Gram (1 Gm) of a cream composition constains:
phenylephrine hydrochloride 10.00 mg 1.00 % diphenhydramine
hydrochloride 5.00 mg 0.5 % benzocaine hydrochloride 20.00 mg 2.00
% tetracaine hydrochloride 10.00 mg 1.00 % zirconium oxide 10.00 mg
1.00 % menthol 7.00 mg 0.7 % camphor 3.00 mg 0.3 % methylparaben
0.80 mg 0.08 % propylparaben 0.20 mg 0.02 % isopropyl alcohol 88.00
mg 8.8 %
This cool, soothing, cream composition is intended to be used as a
topical application of the affected areas. The patients are
instructed to apply the cream on the affected areas two to four
times daily, depending on the severity of the condition, or as
recommended by the physician or dentist. The base of this
composition is very slightly soluble in water for better
penetration of the drug in the affected areas.
EXAMPLE V
Each one Gram (1 Gm) of a cream composition contains:
phenylephrine hydrochloride 10.00 mg 1.00 % diphenhydramine
hydrochloride 5.00 mg 0.5 % benzocaine hydrochloride 100.00 mg
10.00 % tetracaine hydrochloride 10.00 mg 1.0 % oxyquinoline
sulfate 10.50 mg 1.05 % menthol 4.80 mg 0.48 % ichthamol 10.00 mg
1.00 % zinc oxide 10.00 mg 1.00 % petrolatum, lanolin q. s.
This cool, soothing, water insoluble cream composition is intended
for use as a topical applicant on the affected areas. The patients
are instructed to apply the cream on the affected areas two to four
times daily, depending on the severity of the condition, or as
recommended by the physician or dentist. Rinsing with water after
use is discouraged for about 1 hour for better absorption of the
drug by the tissues.
EXAMPLE VI
Each 90 cc (3 fl. oz.) of a toothpaste composition contains:
phenylephrine hydrochloride 900.00 mg 1.00% diphenhydramine
hydrochloride 450.00 mg 0.5 % benzocaine hydrochloride 4,500.00 mg
5.00% tetracaine hydrochloride 900.00 mg 1.00% glycerin (glycerol)1
1,000.00 mg 1.10% propylene glycol 18,000.00 mg 19.80% mineral oil
1,000.00 mg 1.10% peppermint oil 300.00 mg 0.33% saccharine sodium
solution 50% 100.00 mg 1.10% sodium lauryl sulfate 1,500.00 mg
1.65% dicalcium phosphate (in fine powder) 54,000.00 mg 59.40%
sodium carboxymethylcellulose 120 H 900.00 mg 1.00% methylparaben
100.00 mg 0.11% sodium thiosulfate 20.00 mg 0.02% distilled water
q.s. 90 cc.
This composition is intended to be used as a toothpaste. The
patients are instructed to squeeze approximately 1 inch of the
toothpaste on a toothbrush and gently massage the affected areas as
teeth are brushed for about 1 to 2 minutes, and expel the remainder
without rinsing the mouth for about 1 hour. The procedure should be
repeated three to four times daily, depending on the severity of
the condition, or as recommended by the physician or dentist.
The described tablet or cone composition of Example III was used by
the inventor, Carl M. Kosti, D.D.S., in the treatment of 10
patients who had hyperplasia or hypertorphy associated with severe
pain as a result of extraction of impacted molars. The cone was
inserted into the tooth socket immediately after the extractions on
five patients and other five patients were used as control group
without medication. The patients under treatment with the drug
exhibited no hypertrophy or hyperplasia nor was there any pain
associated with the post extraction healing of the tooth socket.
The control patients exhibited hypertrophy and hyperplasia on the
second day post extraction and pain after the first day. On the
third day the control patients were placed on therapy with this
invention. They were instructed to place the cone into the tooth
socket three times daily and were examined each day for one week.
The second day of therapy showed significant reduction in size of
the traumatized area and almost absence of pain. On the fifth day
of therapy the tissue returned to its pre-extraction, normal size
without any pain and the patients were dismissed.
In the foregoing examples, glycerin is used as a sweetening agent
or vehicle in place of syrups (syrups are contraindicated in
toothpastes due to their high carbohydrate content increasing the
incidence of tooth decay) and to maintain the consistency of the
toothpaste; propylene glycol is used in the formulation as a
diluent and binder and may serve as a substitute for glycerin and
alcohol; methylparaben is used as a preservative due to its
inhibitory action on the microorganisms; saccharine sodium solution
is used as a sweetening agent; pepermint oil is one of the many
essential oils that can be used as flavoring agents; mineral oil in
this invention is used as a diluent; sodium lauryl sulfate is used
as an emulsifier and foaming agent; dicalcium phosphate, due to its
fineness is employed as an abrasive; sodium carboxymethylcellulose
is used as an emulsifier and thickening and suspending agent; and
distilled water in the context of this invention is used as a
vehicle and dilutant.
EXAMPLE VII
A toothpaste was prepared as in Example VI with the addition of the
following ingredient:
Stannous flouride 1 ppm (one part per million)
Stannous flouride and other flouride derivatives such as sodium
flouride, monoflourophosphate, potassium flouride, etc. are
effective anticariogenic substances used in toothpaste to control
tooth decay by their action on the protein portion of the enamel
and dentin making the said protein portions harder and subsequently
more resistent to acid desolution and bacterial invasion. Such
substances are generally used in concentrations of 0.25 to 10
ppm.
Other preservatives and their concentrations that can be used in
lieu of methylparaben in the context of this invention are:
sodium bisulfite 0.05 - 0.25 weight percent sodium benzoate 0.05 -
0.25 do. sodium thiosulfate 0.01 - 0.20 do. chlorobutanol 0.01 -
1.0 do. thimerosal 0.001 - 0.01 do. phenylmercuric acetate 0.001 -
0.01 do.
The following substances are wetting and foaming agents which can
be used to reduce the surface tension of the mucous membrane to
improve penetration of the basic active ingredients. Except as
noted, one or more can be used in place of the sodium lauryl
sulfate of Example VI or as added ingredients in the
formulations:
*benzalkonium chloride
*benzethonium chloride
thonzonium bromide
sulfocolaurate
dioctyl sodium sulfosuccinate
sodium alkyl sulfoacetate
sodium lauryl sarcocinate
*cetyl pyridinium chloride
sodium tetradecyl sulfate
The essential components of the toothpaste composition of this
invention are the alkaloid and the antihistamine each in a
concentration of from about 0.0125 to 5.0 weight percent, the
anesthetic in an amount of from about 0.0125 to 20 weight percent,
an alkaloid preservative in an amount from about 0.001 to 0.5
weight percent, a suspending agent in an amount of about 0.002 to
2.0 weight percent and from about 1 to 21 weight percent of a
moisture retainer, with the balance of the composition being
water.
Suitable compounds for use as the alkaloid preservative are
methylparaben, propylparaben, sodium bisulfate, sodium benzoate,
sodium thiosulfate, chlorobutanol, thimersol and phenylmercuric
acetate. Preferred suspending agent materials are sodium
carboxymethylcellulose, methylcellulose, bentonite, acacia,
sterculia gum and tragacanth. Preferred moisture retainer materials
are glycerin, propylene glycol, sorbital, polyethylene glycol,
diethylene glycol monoethyl ether, polysorbate, monolaurate and
polyoxyethylene sorbitan.
While the toothpaste composition of this invention need only employ
the alkaloid, antihistamine, anesthetic preservative, suspending
agent and moisture retainer components, excellent results have been
obtained from a more balanced toothpaste formulation which
included, in addition to the above components, from about 0.01 to
0.5 weight percent of a sweetening agent, about 0.01 to 1.5 of a
foaming agent and about 30 to 65 weight percent of an abrasive.
Examples of abrasive materials which can be used in this invention
are pumice, calcium carbonate, stannic oxide, dibasic calcium
phosphate, magnesium carbonate and tribasic calcium phosphate.
Suitable sweeteners include sodium cyclamate, calcium cyclamate,
saccharines and sodium saccharine. Suitable foaming agents include
sodium lauryl sulfate, sodium tetradecyl. sulfate, sodium lauryl
sarcocinate, dioctyl sodium sulfosuccinate sulfocolaurate,
thonzonium bromide, methyl benzathonium chloride,
dichlorobenzalkonium chloride, dichlorobenzathonium chloride, and
cetyl pyridinum chloride.
Because the vasoconstrictor-antihistamine-anesthetic combination of
this invention has a long duration of action, administration in the
morning and at bedtime is generally recommended. Some patients may
require treatment more frequently, especially where hypertrophy or
hyperplasia or tissue enlargement is of severe nature or where more
rapid reduction in size of tissue is indicated. In that case
typical application of the drug three times a day is suggested: in
the morning, at noon, and at bedtime.
The suggested dosage of the vasoconstrictor is between 0.0125
percent and 5 percent and that of the antihistamine ranges from one
half to equal concentration of the vasoconstrictor employed. The
ratio of vasoconstrictor to antihistamine in a typical example of
this invention is either 1:0.5 or 1:1. The concentration of
anesthetic should be between 0.0125 percent and 20.0 percent by
weight of the composition.
The recommended dosages of the vasoconstrictors are:
For adults and children over six years of age:
Severe hypertrophy or enlargement Fluid composition 0.5 - 2.5%
Paste composition 1.0 - 5.0% Mild to moderate hypertrophy or
enlargement Fluid composition 0.125 - 0.5% Paste composition 0.25 -
0.75% Daily oral hygiene and prophylaxis Fluid composition .015 -
0.125% Paste composition 0.015 - 0.125%
For children six years of age or younger:
Severe hypertrophy or enlargement Fluid composition 0.0125 - 0.25%
Paste composition 0.05 - 0.25% Mild to moderate hypertrophy or
enlargement Fluid composition 0.0125% - 0.025% Paste composition
0.0125% - 0.125% Daily oral hygiene and prophylaxis Not generally
recommended
These concentrations of the vasoconstrictor are only by way of
example and recommended dosage and do not limit the percentage
concentrations within the limits of the given examples. People
knowledgeable in the arts of compounding pharmaceuticals may with
few trials arrive to a preferred concentration of the active
ingredients falling within the range of 0.0125 percent and up to 5
percent.
The use of sympathominetic amines in combinations with
antihistaminic agents for treatment of hyperplastic or
hypertrophied and enlarged tissue has never been suggested or
implied before; the mode of action of this combination is different
than that obtained from either agent used alone. While the
sympathomimetic amines have pharmacodynamic action on the
chemoreceptors of the endothelial cells of the capillary membranes
resulting in a physiological antagonism of the effects of the
histamine on the effector cells, the antihistaminics prevent the
access of histamine to its receptor site in the cells by
competetive inhibition without causing a cellular response or
chemical reaction or antagonism between the histamine and the
antihistaminic agent. Further, vasoconstrictor-antihistamine
combination employed in this patent virtually eliminates any side
effect produced by either agent used alone; the sedative effect of
the antihistaminic agent will counteract the stimulant effect of
the vasoconstrictor. Finally, I am not aware of employing
vasoconstrictor-antihistamine combination in high acid or high
alkaline pH as described herein due to the precipitation of the
alkaloids and the antihistamines, by the alkaline compounds;
however, I have discovered that concentration of more than 10
percent of alcohol or glycols such as glycerin or propylene glycol,
will prevent the said precipitation in either the fluid or paste
compositions.
In addition to the foregoing, I am not aware of anyone suggesting
or advocating a process or a composition for the treatment of pain
associated with hypertrophy or hyperplasia and oral tissue
enlargement. Treatment of the pain symptom is just as important to
the comfort and the well being of the patient as is the treatment
of the condition itself. This invention deals not only with the
therapeutic treatment and the prevention of oral tissue enlargement
but it also relates to the aleviation of the pain phenomena which
is an important and integral part of the entire process of tissue
differentiation and proliferation expected with this condition.
Needless to say, pain is the first symptom most patients afflicted
with this condition will experience and the need for its treatment
is obvious. Topical anesthetics used alone are not as effective in
the treatment of pain associated with tissue enlargement as would
two topical anesthetics such as benzocaine and tetracaine combined
with a sympathomimetic amine and a antihistamine. Local anesthetic
agents such as benzocaine and tetracaine although are classified as
anesthetic drugs they are in their pharmacologic action analgesic
since by definition anesthesia is a state of depressed
consciousness with inhibition or abolishment of pain and analgesia
is a state of inhibition and abolishment of pain without loss of
consciousness when the drugs are used systemically. Topical
application of an anesthetic agent will produce insensitivity or
insensibility to pain in a circumscribed area without central
nervous system depression even when high concentrations of the drug
is employed, therefore the terms anesthesia and analgesia or
anesthetic drug, or analgesic drug are used interchangeably to
indicate insensibility or abolishment to pain when these drugs are
used topically on the oral tissue.
This invention has been described in detail with particular
reference to preferred embodiments thereof, but it will be
understood that variations and modifications can be effected within
the spirit and scope of the invention. The disclosure therein is by
way of example and included in the invention are all modifications
and equivalents falling within the scope of the appended
claims.
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