United States Patent (19) [11] 3,832,460 Kosti (45) Aug. 27, 1974

54 ANESTHETIC-VASOCONSTRICTOR- 3,574,859 4/1971 Kosti...... 424/330 ANTHSTAMINE COMPOSITION FOR THE FOREIGN PATENTS OR APPLICATIONS REEMENT OF HYPERTROPHED ORAL 5,885M 3/1968 France...... 424/54 OTHER PUBLICATIONS 76 Inventor: Carl M. Kosti, 704 Foxhall Rd., Bloomfield Hills, Mich. 48013 Chemical Abstracts, Vol. 65, entry 9535e, 1966. 22 Filed: Mar. 19, 1971 Primary Examiner-Richard L. Huff 21 Appl. No.: 126,256 Attorney, Agent, or Firm--Gerald P. Dundas 63 Related U.S. Application Data 57) ABSTRACT (63) sinual-ing o, St. S. 8. July 2. A composition for the treatment of hypertrophied and continuation-in-part of Ser. No. 742,535, July 5, hyperplastic oral tissue and the pain phenomena asso 1968, abandoned. ciated with this condition. The composition contains as essential ingredients thereof one or more alkaloids, (52) U.S. C...... 424/54 such as the sympathomimetic amines, which are vaso 58) Field of Search...... A61k/7/16; constrictors and effect vasoconstriction of the oral tis 424/49-58 sue, an antihistaminic agent which interfers with the access of histamine to the endothelial cells of the cap 56 References Cited illary membrane, and a topical anesthetic to relieve UNITED STATES PATENTS pain. 3,514,513 5/1970 Bechtold...... 424/54 9 Claims, No Drawings 3,832,460 1 2 ANESTHETC-VASOCONSTRICTOR an increase in the number of polymorphonuclear nu ANTHSTAMINE COMPOST ON FOR THE trophils and increase in size or number of cells. The TREATMENT OF HYPERTROPHED ORAL TISSUE number of open or dialated capillaries is also increased. The main feature of this condition is the increase in size 5 of the tissue which is usually not present at the begin RELATED APPLICATIONS ning of inflammation. This application is a continuation-in-part of my co In fibrous hyperplasia the enlarged tissue is firm, pending application Ser. No. 829,793, filed July 2, dense, insensitive, resilient, and clinically shows granu 1969, entitled “Process for the Treatment of Hypertro lar appearance. Microscopically, the fibrous tissue is phied Gums" now U.S. Pat. No. 3,574,859, which ap O well differentiated with many young fibroblasts pres plication is a continuation-in-part of my application ent. There is decreased in number of polymorpho Ser. No. 742,535, filed July 5, 1968, now abandoned. nuclear neutrophils and open capillaries; the epithe lium is slightly hyperplastic and mildly hyperkeratous BACKGROUND OF THE INVENTION and hornified. Lamina propria, the submucous layel 15 below the epithelium, shows proliferation of the fibro Almost all practicing dentists and most physicians, blasts among which inflammatory cells are present. especially those in the field of neurology, otopharyn Fibrosis is a condition characterized with firm, nodu gology, allergy, internal medicine, and related special lar, fibrous connective tissue. Microscopically, the pic ties have at one time or another in the normal course ture is one of avascular, extremely differentiated bun of their practice encountered patients exhibiting hyper 20 dles of fibrous material with no inflammatory cells or trophy or hyperplasia of the oral tissue. Enlargement in open capillary present, or very few at best, in the tis the size of the oral tissue can be produced either by hy Sule.S. pertrophy (increase in the size of each cell) or by hy It becomes apparent now that inflammation and hy perplasia (increase in the number of cells) or by both perplasia or hypertrophy are different and distinct con phenomena together. It is usually difficult to differenti 25 ditions with inflammation at times, especially at the ate clinically whether tissue is enlarged from hypertro onset of the pathologic process, being associated with phy or hyperplasia or both, and for this reason the hyperplasia or hypertrophy, inflammation being secon terms are used often interchangeably. Only microscopi dary to hyperplasia or hypertrophy. Hyperplasia or hy cally may the differentiation be made. pertrophy is always manifested in enlargement of tissue From a clinical point of view, causes of oral tissue en whereas inflammation may or may not, and usually is largement can be considered of two general types of tis not at the beginning stages, be manifested in enlarged sue and may be termed "inflammatory hyperplasia' tissues. and "fibrous hyperplasia." At the onset of the enlarge Hyperplasia or hypertrophy of the oral tissue may ment there is usually a true inflammatory swelling vary in degree from a slight increase in tissue bulk to which microscopically appears as granulation tissue 35 definitely disfiguring enlargement, and may be grouped containing varying amounts of polymorphonuclear leu into three classes: (1) small enlargement associated cocytes. If the hyperplastic process persists, there is dif with some local irritations on tissues predisposed to fi ferentiation and proliferation of tissue cells with resul brous poliferetion, (2) idiopathic fibrous hyperplasia, tant increase in size or in number of cells, fibrosis of tis and (3) those caused by local application or systemic sue usually takes place, the fibroblasts multiply rapidly, 40 intake of drugs and other chemical agents, such as di connective tissue is formed, the inflammatory cells dis phenylhydantoin. appear and finally the tissue becomes characteristic of dense, avascular tissue. Clinically this transition is char CAUSES OF ORAL TISSUE ENLARGEMENT acterized by decreasing hyperemia and advancing indu A. LOCAL INFLAMMATORY, IRRITATING AND ration of the hyperplastic tissue. The schematic repre 45 TRAUMATIC FACTORS sentation of the pathologic process in transition from 1. Poor oral hygiene, accumulations of calculus initiation of inflammation to fibrosis may be illustrated 2. Malposed teeth, faulty contact points 3. Unusual toothbrush habits inflammation inflammatory hyperplastia 4. Occlusal overfunction fibrous hyperplasia fibrosis 50 5. Irritation from ill-fitting crowns, clasps, prosthetic The chief distinguishing clinical and microscopic or orthodontic appliances signs between the above stages are: 6. Mouthbreathing Inflammation is characterized with immediate dila B. SYSTEMIC PREDISPOSING FACTORS tion response of the capillaries to the chemical or phys 1. Endoctrine ical irritants and the resultant changes in capillary 55 a. Puberty physiology, with increase in the number of open and b. Menstration and pregnancy dilated capillaries supplying the area and increase in c. Hypothyroidism and pituitary disfunction capillary filtration of fluids. This state exhibits no cellu d. Diabetes lar change nor increase in size of the tissue and is the e. Gonadal disturbances beginning of edema. Microscopically, there is increase 60 2. Nutritional in number of leucocytes, especially polymorphonuclear a. Scurvy neutrophils, in the tissue fluid with no change in the b. Subclinical nutritional deficiencies of mixed cellular configuration. types, including B complex Inflammatory hyperplasia is characterized with soft, 3. Blood dyscrasias hyperemic, edematous, or cyanotic, sensitive to touch, 65 a. The Leukemias - particularly monocytic and easily bleeding tissues which are beginning to enlarge myelogenous in size clinically. Microscopically, this condition shows b. Polycythemia vera 3,832,460 3 4 c. Cooley's amenia "all or none' principle - even a small amount of di 4 Drugs phenylhydantoin will exert the same irritating effect on a. Diphenylhydantoin (Dilantin) sodium the tissues or it will not effect the tissues at all. There b. Barbituates fore, some metabolic changes occur at the tissue level 5. Idiopathic forms that prevents reabsorption of the diphenylhydantoin by a. Diffuse fibromatosis of the gums the venous circulation and consequent elimination by C. POST EXTRACTION SWELLING the kidneys in the urine, making possible the retention Hypertrophic or hyperplastic oral tissue may be con of the diphenylhydantoin sodium complex in the inter fined to one part of the mouth, such as in the case of cellular substance to initiate fibrosis. Hypertrophy and post extraction swelling, or it may extend over the en O hyperplasia of the oral tissues continues to attract inter tire oral tissue; it may be confined to the gingival mar est in the dental profession especially in periodon gin or enlarge to the extent of the entire oral cavity tis tology, because of the lack of treatment for this condi sue from the gingiva to the buccal and lingual reflec tion and the high percent of occurrence in patients tions and to the tonsilar and pharyngeal areas. The ini under treatment with diphenylhydantoin for the con tial clinical picture usually exhibits and etiological fac 15 trol of convulsive seizures. The overwhelming gingival tor of congestion with edema and hyperemia followed oral tissue reaction to this drug necessitates more and by less of the inflammatory character and thickening more effect on the dental profession to treat this condi and fibrosis of the connective tissue layer if the causes tion as a serious one since heretofore there are no bio of oral tissue enlargement are allowed to persist. chemicals available to aleviate this condition Many theories have been postulated for the treat 20 thereapeutically; only surgical intervention or taking ment of hyperplasia and hypertrophy of the oral tissue; the drug away from the patient; will provide temporary treatment ranging from the use of diuretics, steroids, relief. Complete removal of the teeth will usually result anti-inflammatory agents, and other biochemicals with in total elimination of this problem. questionable results. The treatment of choice accepted Local or systemic irritation, be it chemical such as by most clinicians knowledgeable in the art of perio 25 diphenylhydantoin sodium or physical such as faulty dontology is gingivectomy (surgical excission of the hy dental restorations and prosthesis, will initially start in pertrophied or hyperplastic tissue) if the condition is edema and gradually progress to fibrosis unless there is not too severe and complete clearance of teeth (full some sort of thereapeutic intervention between the two mouth extraction) if the enlarged tissue interferes with points to prevent the extreme - fibrosis. Edema can, patient's mastication. Heretofore there is no known 30 and usually does, precede hypertrophy and hyperplasia therapeutic treatment for the cure or control of hyper and finally fibrosis, but it is not a part of the fibrous plasia or hypertrophy, whether associated with diphe process itself, edema being a condition characterized nylhydantoin sodium or other irritating causative fac with unusual accumulation of extravascular fluid in the tors, and surgical excission of the enlarged tissue tissues. The causative factor in production of edema is around the teeth is about the only reliable treatment; 35 the apparent imbalance between the transudation of however, recurrence of hyperplasia or hypertrophy of fluid from the circulation and its return by the vascular the oral tissue is certain to reappear after a few months. system. Exchange of water and solutes across the capil Complete clearance of the teeth is necessary if the con lary membrane occurs by filtration at the artetiolar end dition is severe. This invention relates to a process and of the capillary bed and reverse flow, or absorption, at composition for treatment of the enlarged oral tissue 40 the venous end. The two most important factors that which has not been suggested before and is novel in its influence the rate of fluid and solutes across the capil pharmacodynamic action on the enlarged tissue. lary membrane are tissue tension and capillary permea The mode of diphenylhydantoin sodium action on bility. the enlarged tissue is diversified and complicated and Diphenylhydantoin sodium was introduced into med certain cytologic actions are not clearly elucidated. 45 icine for symptomatic treatment of epileptic seizures However, the resultant enlargement of the oral tissue and has become the drug of choice for treatment and due to this drug is similar clinically to the enlargement control of convulsive conditions due to its non hypnotic caused by other chemical and physical irritants. For effect on the central nervous system. The primary con this obvious reason the pharmodynamic action of the cern of the dental profession to this drug is the effect drug diphenylhydantoin on the oral tissue is empha 50 it has on the oral gingival tissue causing fibrous prolif sized in this patent application but in no way it should eration which results in fibrous enlargement of the restrict the use of this invention only to the enlarge gums. Gingiva is that portion of the oral mucous mem ment caused by this drug. brane which surrounds the teeth and is not attached to Many studies have been made in regard to the causal the underlying alveolar bone. It differs from the mu relationship of diphenylhydantoin sodium with oral tis 55 cous membrane in that the epithelium is thicker and sue hyperplasia or hypertrophy and the resultant fibro hornified to better resist the constant stresses applied sis of the said tissues with all investigators agreeing that to the tissue during mastication. Once the teeth are re diphenylhydantoin hyperplasia is essentially the result moved the gingiva ceases to exist; then it becomes at of irritation of the gingival tissue around the teeth by tached to the alveolar bone and the epithelium looses the drug when taken systemically. Hyperplasia or hy 60 its hornification. Some periodontists hold the gingiva to pertrophy does not occur in the edentulous areas which be different tissue from mucous membrane and this dif indicates that the teeth serve as nodi of diphenylhy ferentiation is particularly true in case of fibrous hyper dantoin sodium irritation. Almost all investigators plasia due to dilantin since the drug affects only the gin agree that there is no relationship between the amount 65 giva, the tissue around the teeth, and has no effect on of diphenylhydantoin intake and the degree of resultant the rest of the mucous membrane of the mouth. fibrous hyperplasia. Perhaps this fact indicates that the Diphenylhydantoin sodium when taken orally, in ei action of diphenylhydantoin on the tissues works on the ther flavored or oil vehicle, is partially dissolved in the 3,832,460 S 6 intestine and readily absorbed by the circulation and Alkalinity having pH (or more precisely pCH) of 7.4 is carried throughout the body, especially in the areas not high enough to keep the diphenylhydantoin sodium demonstrating high metabolic rate of the tissues such present in the tissues in solution but is high enough to as brain, the hair follicle, the oral gingiva etc. Since the prevent disaggregation of hyaluronic acid by the car alkalinity of the gastric fluid and of the oral tissues is bonic acid which is produced during tissue metabolism. not high enough to provide complete dissolution of di The viscous consistency of the ground substance keeps phenylhydantoin sodium (the pH must be about 11.7 to the conjugate of the diphenylhydantoin - glucuronic obtain saturated solution) the unchanged drug, due to acid bound or captured within the tissue spaces pre its affinity for the tissues in high metabolic rate, finds venting the conjugated complex from being absorbed its way into the extracellular ground substance of the O and subsequently excreted by the venous circulation. oral gingiva. Once in the ground substance of the gin Retention of the diphenylhydantoin complex in the giva diphenylhydantoin conjugates with glucuronic ground substance enables the drug to prolong and in acid - a metabolite of hyaluronic acid, and in this form tensify its stimulatory effect on the fibroblasts resulting it is excreted in the urine. The metabolites found in the in gingival fibrosis. urine are conjugated with glucuronic acid. The conju 15 gation reaction involves combination of a metabolite of SUMMARY OF THE INVENTION diphenylhyantoin with some other substance, such as This invention pertains to compositions uniquely the metabolite of hyaluronic acid -glucuronic acid, fol suited for the treatment of hypertrophied or hyperplas lowed by the elimination of the resulting conjugate. tic tissue and the pain associated therewith and which The dissolved diphenylhydantoin in the ground sub 20 comprise in combination a vasoconstricting alkaloid, stance of the oral gingiva is easily dissociated even by an antihistamine, and an anesthetic. The preferred al weak acids such as carbon dioxide (CO2), which is the kaloids for use in this invention are aromatic amines biproduct of metabolism in the tissues whenever the tis having between about 6 to 10 carbon atoms and ali sues are active in response to a chemical or physical phatic amines having between about 4 to 7 carbon stimulant, with the regeneration of 5,5- 25 atoms. The preferred antihistaminics are those of the diphenylhydantoin. The metabolities of diphenylhy skeletal structural formula: dantoin, hydantoic acid and amino acid, by the action of carbon dioxide and the subsequent increase of car bonic acid (HCO3) are regenerated to the 5,5- R R diphenylhydantoin which is made available for more 30 / -CH-CH-N conjugation with glucuronic acid and therefore binding R. R in the ground substance of the gingiva. This complex, unless eliminated by the urine, will prolong the irrita wherein X may be oxygen, nitrogen or carbon, and R, tion of the fibroblasts resulting in secretion of collagen R" and R'' are either aryl, alkyl or aralkyl groups. for formation of fibrous tissue bundles. It now becomes 35 The antihistamine should have a minimum molecular apparent that diphenylhydantoin in the oral tissues un weight of about 150, and each of the aryl, alkyl or aral dergoes a vicous cycle of disassociation and regenera kyl groups should contain in the range of about 2 to 16 tion. carbon atoms. If X in the structure shown above is ni Another important characteristic of diphenylhy trogen, the resulting compound may be viewed as an dantoin action in the gingival tissue is that it stimulates 40 ethyleadiamine derivative; if oxygen, as an aminoalkyl liberation of histamine and histamine-like substances ether, and if carbon as an alkylamine. Attached and reduces the amount of serotonin. Histamine is through the carbon, oxygen or nitrogen is the so-called found in the cells of most connective tissue and its pri nucleus of the antihistaminic drug. Preferably, this nu mary function upon liberation is to vasodialate the arte cleus should consist of a minimum of two aryl or aralkyl rioles and capillaries thereby bringing more circulation 45 groups. to the injured area and to lower the capillary permea The anesthetics preferred for use in this invention are bility. Diphenylhydantoin in regard to the capillary the amino esters of aromatic acids and aminoacyl am membrane has dual effect; initially it stimulates the ides of aromatic acids. Such compounds will generally chemoreseptors of the endothelical cells to secrete his contain a maximum of about 26 carbon atoms. tamine and secondly it acts directly on the smooth mus 50 The compositions of this invention should contain cle of the arteries and arterioles causing lowering of the vasoconstricting alkaloidal and antihistaminic each membrane permeability. Diphenylhydantoin and hista in an amount of about 0.0125 to 5.0 percent by weight mine both jointly vasodialate the capillaries and in based on the weight of the entire composition. When crease the capillary membrane permeability allowing the alkaloid is present in an amount in excess of about diffusion of not only crystalloids but also colloidal sub 55 1.0 weight percent then the weight ratio of alkaloid to stances from the vascular system and into the tissue antihistamine is preferably about 1:05, that is, the spaces. This particular action of diphenylhydantoin, va amount of antihistamine employed is about half that of sodilation and alteration of capillary membrane perme the alkaloid. When the concentration of alkaloid is less ability, is essentially the reason why edema is preceding than about 1.0 percent, then good results have been or superimposed condition to fibrosis of the gingiva in found using an equal amount of the antihistamine, or diphenylhydantoin therapy. an alkaloid to antihistamine ratio of 1:1. These ratios The outer layer of the mucous membrane - the hor are not absolute and are being set forth only as a guide. nified epithelium, is acidophil in character and the un derlying submucous layer is alkaline having pH of ap The amount of anesthetic compound employed is, of proximately 7.4. The alkalinity of the submucous layer, 65 course, very dependent on the compound selected. For where the ground substances are found, maintains the example, tetracaine hydrochloride because of its rapid consistency of the hyaluronic acid gel-like and stable. absorption by the blood and relative toxic reaction 3,832,460 7 8 when ingested in large amounts, should be used in mini composition will retard the excretion of the collagen mal amounts. Good results have been achieved in the material by the fibroblasts (fibroblasts are germinating treatment of pain associated with hyperplasia or hyper cells, or precursors, giving rise to new fibers) thusly trophy with concentrations in the range of about minimizing, if not completely eliminating the possibility 0.0125 to 5.0 weight percent. On the other hand, ben of fibrosis. The acidity, or the alkalinity, of the compo zocaine is relatively free of any side effects and toxic sition of this invention will gradually convert the newly reactions, even when used in high concentrations, and formed collafenous fiber into more easily reactive gela has been used successfully at concentrations in the tin which is readily digestable by tissue enzymes and re range of 0.0125 to 20.0 weight percent. Accordingly, moved by the circulation. The composition of this in the anesthetic compound should be present in an O vention will further gradually break the bonds linking amount of about 0.0125 to 20.0 weight percent based parallel polypeptide chains to single peptide chains of on the weight of the entire composition. gelatin. The compensatory alkalinity of the tissue fluid DESCRIPTION OF THE PREFERRED during the treatment with the compositions of this in EMBODIMENT vention is opposed by the buffering system of the inter 15 cellular fluid and the excess alkalinity will be neutral Application of the composition of this invention to ized by the carbonic acid of the tissue fluid in order to the oral tissues, for example, either in mouthwash or keep the proper bicarbonate/carbonic acid ratio 20:1 toothpaste formulations, will readily penetrate the at pH 7.4. outer keratinous epithelial layer, break the electrical The vasoconstrictor component of the compositions polarization that exists between the acidic epithelium 20 of this invention, such as the sympathomimetic amine and the alkaline submucosa and diffuse into the deeper phenylephrine hydrochloride, upon entrance into the submucous tissues. Brushing or massaging of the gums ground substance of the tissue acts directly on the will express the air bubbles from the epithelium, partic chemoreseptors of the endothelical cells of the capil ularly the air bubbles in the ducts of the secretory lary membrane. It causes swelling of the cells thereby glands which extend deep into the submucosa, provid 25 decreasing the lumen of the capillaries and restoring ing entrance and facilitate absorption of the drug. Once the patency of the membrane. This vasoconstriction of the composition gains entrance in the ground substance the arterioles and capillaries (the venuoles are not af. of the enlarged tissue its alkalinity will readily neutral fected to an appreciable degree) stops the escape, or ize the acid present during the tissue activity resulting leakage, of the larger molecules of proteins and the un in metabolic alkalosis. This neutralization tends to in changed diphenylhydantoin sodium from the circula crease the pH of the tissue fluid from 7.4 to about tion and into the tissues thereby restoring the normal 10-12, depending on the dissociation of the alkaline balance of vascular and extravascular fluid and electro composition to free hydroxyl group and the amount of lytes exchange. The prevention of diphenylhydantoin carbonic acid present in the tissues for neutralization. escape into the tissues and the subsequent elimination Increased alkalinity of the tissue fluid, especially 35 of the metabolites of diphenylhydantoin from the tis around pH 1 1-12, results in increased dissolution of di sues by the venous circulation, reduces the amount of phenylhydantoin either in the conjugated or metabolic the drug available for stimulation of the fibroblasts to form, thusly eliminating the drug by the venous capil secrete collagenous material and form the insoluble fi lary system. The change of tissue acidity affects the hy bers. Decrease of diphenylhydantoin metabolites from drolysis of ground substance - hyaluronic acid. On hy 40 the tissues liberates the calcium ions from the complex drolysis, hyaluronic acid yields equimolar amounts of diphenylhydantoin-calcium conjugate allowing it to re d-glucoseamine, d-glucuronic acid, and acidic acid and turn to the cement material of the endothelial cells of is believed to contain a repeating disaccharide unit the capillary membrane and active cells. The vasocon comprising N-acetylglucoseamine glucuronide. Hydro striction of the capillaries deprives the hypertrophied lysis of the glucuronic acid decreases the viscosity of or hyperplastic cells from nutrition and subsequent de the ground substance freeing the diphenylhydantoin crease either in the size of the cells themselves or the portion from the diphenylhydantoin-glucuronic acid number of cells. In hypertrophy or hyperplasia, espe conjugate to be dissolved by the alkaline composition, cially at the initial stages, there is increase in the num particularly when the pH is 11-12, and subsequently ber of capillaries which is evident under microscopic eliminated by the kidneys. The dissolution of the drug 50 examination. The vasoconstrictor, for example, phenyl diphenylhydantoin in the tissue fluid will result in de ephrine hydrochloride, by virtue of its action on the en crease of stimulatory effect the drug has on the fibro dothelial cells of the capillary membrane decreases and blasts therefore lessening the chance for fibrosis. sometimes virtually eliminates, particularly the newly Another important function of this invention, in acid formed capillaries, from being able to supply the hyper as well as alkaline formulations, is the effect it has on 55 trophied or hyperplastic cells with nutritious materials the collagen material of the oral tissues. Collagen is the therefore practically "starving' the new cells to death. most abundant protein material in any connective tis This event is especially true before fibrosis is allowed sue. The fibrous connective tissue contains 63 percent to proceed. water, and 31.6 percent collagen with small amount of The antihistamine, as for example, antazoline hydro elastin and mucoids. Collagen is a tough, inert, insolu 60 chloride, upon entrance into the ground substance of ble in water fiber but slowly converted to gellatin by the oral tissues prevents the access of histamine liber boiling water, dilute acids and alkalies. Diphenylhy ated by the excitatory effect of diphenylhydantoin on dantoin, being an irritant, stimulates the fibroblasts to the tissue cells, to its receptor site in the endothelial secrete collagenous material which is precipitated out 65 cells of the capillary membrane and thereby blocks the side the cells forming interconnected bundles of the in response of the effector cell to the amine. The antihis soluble threads. This process of fiber formation is tamine possesses no pharmacodynamic action; it does called fibrosis. The acid or alkaline character of my not react to have antagonistic action with the hista 3,832,460 9 10 mine. The antihistamine occupies the receptor site of compounds, the majority of which have the structural the endothelial cells without causing a cellular re formula: sponse. This characteristic of the antihistamine used in R R my formulations potentiates the physiological antago N X-CH-CH-N nism of the sympathomimetic amine to the effects of 5 / the histamine on the capillary membrane resulting in R R more profound vasoconstriction. The pharmacody in which it is apparent that core of the structure is a namic action of, for example the phenylephrine hydro substituted ethylamine, which is also present in hista chloride - antazoline hydrochloride combination is mine. It is most likely that it is this portion of the mole more intense than that produced by either agent used O cule which competes with histamine for cell receptors. alone. Phenylephrine hydrochloride gives a very rapid In most instances, the ethylamine grouping is present as onset of reduction of local oral tissue swelling while a straight chain, but in a few it is part of a ring struc antazoline hydrochloride prolongs the reduction in the ture. size of the oral tissue by its direct action on the capil Nearly always, the substituted ethylamine of hista lary membrane. 15 mine antagonists is teritary, with the activity of secon The most beneficial advantage of vasoconstrictor dary or primary amines being greatly attenuated. Fur antihistamine combination is virtually elimination of thermore, optimal substituent groups on the amine in any side effects produced by either agent used alone. most senses is N-dimethylalkyl. Generally N-diethyl. The sedative effect of the antihistamine will counteract compounds are less active and more toxic. Occasion the stimulant effect of the sympathomimetic agent. ally, the substituted amine is incorporated in a hetero In obtaining the new and novel treatment, this inven cyclic ring without loss of activity. Quarternization of tion makes use of certain alkaloid compounds or sub the tertiary amine diminishes but does not abolish ac stances which are sympathomimetic amines, and which tivity. possess among other properties those of serving as de As noted earlier in this application, X in the structure congestants or vasoconstrictors effecting shrinkage of 25 may be oxygen, nitrogen or carbon and it is not possible the overgrown oral tissues. Preferred are aromatic to make any great distinction between these with re amines having been 6 to 10 carbon atoms, and aliphatic spect to antihistaminic activity. In addition, the follow amines having a total of between 4 to 7 carbon atoms. ing can be associated with antihistaminic activity; ami Some examples of useful compounds are: noketones, secondary aminoalcohols, alkylesters and A. Aromatic Nucleus: I. Unsubstituted: l. Phenylethylamine------C.H.CH.CH-NH2 2. Phenylethanolamine CHs.CHOH.C.H.NH 3 . Amphetamine------CEs. CH2CHCH.NH 4. Dextro-amphetamine Isomer of amphetanuine. 5. Methamphetamine-- CHCH.CHCH-NHCH 6. Mephenter nine---- - CHs. CHCHCHH.CH 7. Phenylpropanolamine- CHs...CHOH.CHCH3NH2 8. Ephedrine------... CHCHOH. CHCH3NHCH3 9. Naphazoline------CHCH-NH-H, N CH 10. Phenylpropylmethylamine------C6HsCHCHs. CH-NHCHs II. Monosubstituted: 1. Tyramine------IO.CsII.CH2CH2.NH 2.5-hydroxytriptamine------3. Synephrine------HO.C.H.CHOH.CH-NHCH3 4. Phenylephrine------CIOI.CIOHCH-NHCH 5. Hydroxyamphetamine- - HO.C.H. CHCHCH-NH2 6. Paredrinol------HO.C.H.CH2CHCH-NHCH 7. Methoxyphenannine------CHO.C.H.CII. CHCH3NHCH3 lil. Disubstituted: 1. Epinine------...-- (HO).C.C.C H.NHCH3 2. Lewarterenol (HO). CH3CHO.CH2.NH2 3. Epinephrine---- (IO). CHs...CHOII.CH-NHCH 5.4. Methoxamine---Oxymetazoline...I.I.I.I.I.I.I. 6-5345-butyl-3(2-imidazoline-2-yi methyl)2,4- dimethylphenol. B. Alight1. Tuaminopheptane---- Nucleus: ------CH3(CH2)CHCH-NH2 2. Methylhexaneamine CHCH.CHCH.CH.CHCH3.NH; 3. Cyclopentamine------S CHCHCHs.NHCH 4. Propylhexedrine.------S H. CHCH3NHCH Ephedrine sulfate, phenylephrine hydrochloride, cy- 60 haloalkylamines. clopentamine hydrochloride, methylhexaneamine hy Attached through the carbon, oxygen or nitrogen is drochloride, and oxymetazolin hydrochloride, are the the socalled nucleus of the antihistamine which should preferred sympathomimetics because they can be em consist of a minimum of two aryl or aralkyl groups or ployed in aqueous, oil and alcohol solutions and in mix their equivalent in a polycyclic ring system, with the tures thereof. They are readily available, relatively sta- 65 nucleus having a minimum molecular weight of 150. ble, do not decompose readily to light, heator air. They Some of the typical antihistaminics are the hydro can be boiled for sterilization, have a long duration of chlorides, citrates, maleates and succinates such as: action and are substantially free of aftercongestion. The antihistamine employed in the compositions of antazoline hydrochloride CHNHCL tripelcnnamine hydrochloride CHNHCL this invention may be any of the commercially available tripelennamine citrate CHNs (CHO)2 3,832,460 2 thonzylamine hydrochloride CHCLNOHCL or as in case of Benzocaine methapyriline hydrochloride CHNSHCL methapheniline hydrochloride CHNSHCL NH NH pyrilamine maleate ChaNOCHO chiorphenamine maleate CHCLN.CHO chlorother CHCLNS pheniramine CHN pheniramine maleate Chan, C.H.O. chlorcyclizine hydrochloride CHCLNHOL diphenhydramine hydrochloride CHNOHCL doxylamine succinate CHNOs COOCH, HCL -- NaHCO3-). COOCH -- NaCL -- HCO phenyltoloxamine citrate CHNO diphenylpyraline hydrochloride CHNOHCL The ability of the undissociated free base to pene phenindamine tantrate CHN thenyldiamine hydrochloride CHNS O trate cellular membranes is the first requisite for anes Antazoline hydrochloride, diphenhydramine hydro thetic activity. Once the neutralization is satisfied the chloride thonzylamine hydrochloride, and chlorphena anesthetic is further dissociated to cationic form which mine maleate are the preferred antihistaminics in this reacts readily with the intracellular constituents of the invention due to their lack of incidence of side action nerve fiber, principally the lipids. This ionization reac and low tissue irritancy; however, any of the above 15 tion may be represented as named antihistaminics may be used in this invention RN -- HOH - RNH -- OH without lowering the potency and the effectiveness of the fluid and toothpaste compositions. where now the free base is in form of cations and has the tendency to escape from solution into the state of As indicated above, this invention is concerned with 20 reducing the size of enlarged oral tissue and alleviation absorption on cellular constituents. Once the equilib of pain associated with hyperplasia. The reduction in rium of the neutralization reaction is reached, the free size of the tissue is effected by the action of the sympa anesthetic base becomes hydrophobic and lipophilic to thiomimetic amine directly on the chemoreseptors of form a temporarylebile union with the axoplasm. This the endothelial cells of the capillary membrane causing 25. complex temporary lebile structure interferes with vasoconstriction of the capillaries and arterioles, and breakdown of acetylchloline by the enzyme cholines by the competitive inhibition of the antihistaminic drug terase. Acetylcholine is a chemical mediator present in on the histamine by occupying the receptor site of the the nerve tissue as a non diffusable, physiologically in endothelial cells without causing cellular response. The active form and not susceptible to hydrolysis. In this pain is alleviated by the action of the anesthetic or the 30 form it is referred to as a procursor or bound acetylcho analgesic on the nerve endings of the enlarged tissue. line which is found in the individual nerve fibers and at The anesthetic employed must be capable of block the synapse. Upon stimulation of a nerve to conduct an ing nerve conduction when applied locally to nerve tis impulse, acetylcholine is liberated by each individual sue and should not be irritating and must produce anes cell of the nerve fiber to conduct and transmit an im thesia without causing damage to nerve structure. 35 pulse from one cell to another all along the axon and Generally, topical anesthethics are weak organic across the myoneural junction to the muscle affected bases which are poorly soluble in water. However, by that particular nerve causing excitation. To prevent these bases will react with acids, particularly hydro continuous and rapid firing of stimuli along the axon, chloric acid, to form water soluble salts which are suit acetylcholine is almost immediately destroyed by the able for topical application. There is abundant evi 40 enzyme acetylcholine esterase, or simply cholinester dence to show that the neutralization of the acid salt ase. This complex biochemical reaction may be repre and the liberation of the free base are essential for an sented esthetic activity. ACH-esterase Little is known regarding the pharmacodynamics of / -- HOH 45 CH-C-O-CHCH-N* (Ch.), Choline acetylase the topical anesthetics. The drug appears to have a se -- CoA acetate lected affinity for voluntary muscle nerves, propriosep Acetylcholine OH tors, cold and hot, and pressure nerves, etc. The anes thetic apparently passes through the neurilemma and into the axon where it combines with the nerve fiber Hochsch, N-(CH.) 3. -- CHCOOH chemically, altering its function of conductivity. The 50 Choline OH- Acetic acid topical anesthetic will also affect the synaptic transmis sion of nerve impulses possibly by affecting the metab This reaction is reversable under normal tissue condi olism of acetylcholine or competing with it in an en tions so that subsequent to the stimulation of the nerve zyme system. The topical anesthetics are fat-soluble fiber, resynthesis of the end products (choline and and to make the alkaloids water soluble they are dis 55 acetic acid) to the original substance (acetylcholine) pensed as acid salts. occurs in the presence of enzyme choline acetylase and Upon application of the composition of this invention coenzyme acetase. on the oral tissue, the anesthetic salt undergoes three The free base, which has now penetrated the neuri separate but interdependent stages: (1) neutralization, lemma, reacts directly with potassium and magesium (2) hydrolysis, and (3) resynthesis. NEUTRALIZA ions in the axoplasm preventing the resynthetization of TION: acetylcholine by denying enzyme choline acetylase its The neutralization of the anesthetic salt, which is activators. The potassium and magnesium ions are nec strongly acid in reaction, is affected by the sodium bi essary to be present in the substrate for the enzyme carbonate (NaHCO) present in the tissue. The anes choline acetylase to be effective. They are referred to thetic salt is hydrophilic in nature and reacts with the 65 as activators. The enzyme choline acetylase catalyses sodium bicarbonate from the tissue raising the pH of the transfer of acetyl radical from CoA-acetate to cho the environment to over 7.5. The reaction may be rep line which is essential for synthesis of acetylcholine. resented as follows: The free anesthetic base in effect acts as an anti R:NHC -- NaHCO - RN -- NaCL -- HCO3 cholinesterase by the nature of its interference with acid salt free base cholinesterase in breaking down of acetylcholine re 3,832,460 13 14 sulting in prolonged parasympathetic activity. The an the fat in nerve tissue is replaced in 7 days. This ex esthetic effect will last as long as the union of the free plains the slow hydrolysis of the anesthetic solution in base and the lipid constituents of the axoplasm is left the nerve tissue and its rapid destruction in the liver. intact or until the enzymatic accumulation in the nerve Instillation of the composition of this invention in ei tissue, the substrate, is concentrated enough to reverse ther fluid, paste, or tablet form on the oral tissue will the reaction and change the direction of the equilib have three distinct and yet coordinated functions. (1) rium to the side of the hydrolysis of the drug. the action of the sympathomimetic amine on the endo HYDROLYSIS: thelial cells of the capillary membrane resulting in va Following the absorption, benzocaine and tetracaine soconstriction of the said capillary membrane, (2) the are hydrolysed to ethanol and para-aminobenzoic acid O action of the antihistaminic on the histamine in the tis and dimethylaminoethanol and para-amino benzoic sues potentiating the effect of the sympathomimetic acid respectively by the enzyme esterase. The hydroly amine, and (3) the action of the analgesic agent on the sis reaction within the nerve axoplasm of benzocaine nerve fibers of the affcted hyperplastic or hypertro hydrocloride may be represented as phied and enlarged oral tissue resulting in blockage of 15 the sensory pain impulses and temporary anesthesia. In NH NH addition, the vasoconstriction caused by the sympatho mimetic amine will prolong the effect of the topical an Benzocaine esterase esthetic due to the resultant decrease in the absorption - HOH of the anesthetic drug. This decrease in the absorption of the anesthetic drug is significant since it will require COO CHHC, COOH -- CHsOH less amount of the anesthetic to obtain the necessary degree of analgesia, decreases the possibility of toxic and the hydrolysis of tetracaine hydrochloride may be ity, and prolongs the duration of the analgesia. represented as The topical anesthetics, which are analgesic, used in 25 this invention are generally secondary or tertiary amino NHCHCHCH-CH, NH, esters of aromatic acids, or secondary or tertiary aminoacyl amides of aromatic acids, the ester type hav ing the benzoic acid, parabenzoic acid or meta-benzoic acid as the nucleus of the structure with aromatic orali 30 tetracaine esterase phatic substutions of up to 14 carbons atoms each, and COOCHCHN (CH).HCL COOH + the amide type having the xylene or toluene radical as the nucleus of the structures with, again, aromatic or (CH)NCHOHoH aliphatic substitutions of up to 14 carbons each. The The biproducts ethanol and para-amino benzoic acid ester type has the general structural formula: and dimethylaminoethanol and para-amino benzoic 35 acid of benzocaine and tetracaine respectively, are R / inert compounds and are removed from the tissue by R1-COOR-N N routine channels of elimination. Eighty percent of para R amino benzoic acid is excreeted in the urine and only 40 30 percent of ethanol and dimethylaminoethanol is re covered in the urine. The low percentage of the recov where R with its carboxyl group may be benzoic acid, ered alcohols is due to some being changed to aldehyde para-amino benzoic acid, or meta-amino benzoic acid or ketone by the nerve cell protein and as such carbo and R2, Ra and R4 are aromatic or aliphatic radicals of hydrates are used by the nerve as a source of energy 45 up to 14 carbon atoms each. during transmission of an impulse. The respiratory quo The amide type has the general structural formula tient of a metabolizing nerve is very close to 1.0 which suggests that the nerve is utilizing carbohydrates almost R exclusively. R-N-H cogR-N The unhydrolysed benzocaine and tetracaine which 50 enter the blood circulation are rapidly detoxified S.R chiefly by the liver and excreted in the urine by the kid neys. where R is either xylene or toluene substituted and R, RESYNTHESIS Ra and R are aromatic or aliphatic radicals of up to 14 This phase deals primarily with resynthesis of the en 55 carbon atoms. - zyme acethylcholine and the return of the nerve con Some of the typical local and topical anesthetics em stituents to their normal biochemical equilibrium. Clin ployed today are the synthetic products such as ically, this is the so-called wearing-off period; chemi cally, it may be represented as cocaine hydrochloride CHNOHCL 60 procaine hydrochloride CHNOHCL choline acetylase lidocaine hydrochloride CHNOHCL mepivacaine hydrochloride (Carbocaine hydrochloride) HoCHCHN-(CH.) s - CHCOOH -- CoA acetate prilocaine hydrochloride CHNOHC(Citanest hydrochloride) CHCOC H.HŠ-(CH.) pyrrocaine hydrochloride CHNOHCLCHNHCL VJ, 65 butethamine hydrochloride (Monocaine hydrochloride) CHNOHCL The rate at which the lipids of a nerve tissue are ex metabutethamine hydrochloride (Unicaine hydrochloride) changed are relatively slow in comparasion to that of CHNOHCL an active organ such as the liver. Tracer studies with isobucaine hydrochloride CHNOHCL tetracaine hydrochkoride (Pontocaine hydrochloride) deutorium indicate that while 50 percent of the liver CHNOHCL fats may be exchanged in 24 hours, only 20 percent of propoxycaine hydrochloride (Ravocaine hydrochkoride) ChinChCL 3,832,460 15 16 -Continued This composition is intended to be used as a mouth benzocaine CHNO wash, rinse, or gargle. The patients are instructed to BUACANE SUFATE (Butyn Sulfate) swish about one to one half fluid ounce of the solution CHNOHSO, dyclonine hydrochloride (Dyclone hydrochloride) in the mouth for approximately 1 to 2 minutes and CHNO, HCL dibucaine hydrochloride (Nupercaine hydrochloride) expel the remainder. Rinsing with water after usage is CHNOCHL discouraged for at least 1 hour for the obvious reason piperocaine hydrochloride (Neothesin hydrochloride) of better absorption of the drug. The procedure should CHNOHCL phenacaine hydrochloride (Holocaine hydrochloride) be repeated two to four times daily, depending on the CHNO, HCL-HO severity of the condition, or as recommended by the diperodon hydrochloride (Diothane hydrochloride) O CHNOHC physician or dentist. dimethisoquin (Prutargan, Quinist xcaine, Ouotane, Prulargin) CHNO EXAMPLE II naepane (Naepaine, Amylsine) CHNO; 15 Each cc of a spray composition contains: The combination of Benzocaine and Tetracaine hy drochloride was found to be most effective in produc phenylephrine hydrochloride 10.00 mg 1.00 ing topical anesthesia due to Tetracaine's high activity diphenhydramine hydrochloridc 5.00 mg 0.5 benzocaine hydrochloride 0.00 mg 100 % even in very low concentrations and its rapid onset of tetracaine hydrochloride 5.00 mg 0.5 anesthesia and Benzocaine's low solubility. There is a 20 zirconium oxide i0.00 mg ()0 group of local or topical anesthetics characterized by inenthol 0.09 mg 0.009 . camphor 0.98 mg 0.098 , the fact that its members are poorly soluble in water, calamine 9.80 mg 0.98 and Benzocaine is one of them. Due to its insolubility, isopropyl alcohol 95.00 mg 9.5 %, the compounds are not absorbed with sufficient rapid methylparaben 0.80 mg 0.08 25 propylparaben 0.20 mg 0.02 , ity to be toxic and therefore can be applied directly to propellants 873.33 mg 87.33 %, the wounds and open surfaces on the mucous mem brane. For the same reason they remain localized at the This cool, soothing, composition is intended to be site of application for long periods of time, which ac counts for their sustained anesthetic action. In my for used as a spray. The patients are instructed to spray the mulations Tetracaine will produce a very rapid onset of 30 affected area approximately six times (1 cc) with the anesthetic action even in concentrations of less than solution and are discouraged to rinse with water for ap 1.0 percent without any toxic effects and Benzocaine proximately 1 hour after usage. The procedure should will give a sustained anesthetic effect. The vasocon be repeated two to four times daily, depending on the strictor phenylephrine hydrochloride adds to the sus severity of the condition, or as recommended by the tained actions of both topical anesthetic agents by pro 35 physician or dentist. longing the absorption of the drugs by the circulation. Any one, or any combinations, of the above named EXAMPLE III topical anesthetics may be used in lieu of Benzocaine and Tetracaine to produce topical analgesia without Each tablet or cone of the composition contains: departing from the intent and the scope of the inven 40 tion; however, the solubility, toxicity, potency, and ac phenylephrine hydrochloride 50.00 mg 100 % tivity of each individual drug must be considered in the diphenhydramine hydrochloride 25.00 mg 0.5 selection of the topical anesthetic. benzocaine hydrochloride 750.00 mg 5.00 Some other compounds that may be employed as tetracuine hydrochloride 20.00 mg 0.4 45 sodium chloride 19.50 mg 0.39 topical anesthetics are some aromatic alcohols such as glucose 1.00 mg 0.02 . Benzyl Alcohol and Saligenin, quinine salts such as polyethylene glycol 6000 3000.00 mg Quinine and Urea Hydrochloride; chlorobutanol; ethyl d-leucine q.s. 5 Gm chloride; phenolic compounds such as amyltricresol, parachlorophenol, cresol, creosote, eugenol, guaiacol, This water soluble tablet or cone composition is in phenol, thymol and other related organic compounds. tended to be used as an insert or a packaging of the af The compositions of this invention may be fluid, fected areas. In post extraction and post surgical cases paste, spray or tablet preparations of the vasoconstrict the patient is instructed to insert the tablet or the cone or-antihistamine-analgesic combination. The following into the tooth socket or the incission for the effective examples illustrate such preparations. treatment of hypertrophy or hyperplasia and tissue en 55 largement and the associated pain. The procedure EXAMPLE I should be repeated four times daily or as required for Each cc of a fluid composition contains: pain. phenylephrine hydrochloride U.S.P. 10.00 mg .00 diphenhydramine hydrochloride U.S.P. 5.00 mg 0.5 benzocaine hydrochloride 50.00 mg 5.00 tetracaine hydrochloride 10.00 mg .00 benzalkonium chloride 2.00 mg 0.2 saccharinc sodium 0.18 mg 0.018 spearmint oil 0.15 mg 0.05 sodium chloridic 3.90 mg 0.39 sodium thiosulfate ().20 mg 0.02 alcohol 80.00 mg 0.8 distilled water C.S. cc 3,832,460 17 18 on the severity of the condition, or as recommended by EXAMPLE IV the physician or dentist. Each one Gram (1 Gm) of a cream composition con The described tablet or cone composition of Exam stains: ple III was used by the inventor, Carl M. Kosti, D.D.S., in the treatment of 10 patients who had hyperplasia or phenylephrine hydrochloride 10.00 mg 10() % hypertorphy associated with severe pain as a result of diphenhydramine hydrochloride 5.00 mg 0.5 % extraction of impacted molars. The cone was inserted benzocaine hydrochloride 20.00 mg 2.00 %, tetracaine hydrochloride 10.00 mg (X) , into the tooth socket immediately after the extractions zirconium oxide 10.00 mg 00 % on five patients and other five patients were used as ment hol 7.00 mg ().7 A. () canaphor 3.00 mg ().3 *A, control group without medication. The patients under methylparaben 0.80 mg ().08 A, treatment with the drug exhibited no hypertrophy or propylparaben ().20 mg ().02 %, hyperplasia nor was there any pain associated with the isopropyl alcohol 88.00 mg 8.8 %, post extraction healing of the tooth socket. The control patients exhibited hypertrophy and hyperplasia on the This cool, soothing, cream composition is intended to 15 second day post extraction and pain after the first day. be used as a topical application of the affected areas. On the third day the control patients were placed on The patients are instructed to apply the cream on the therapy with this invention. They were instructed to affected areas two to four times daily, depending on the place the cone into the tooth socket three times daily severity of the condition, or as recommended by the and were examined each day for one week. The second physician or dentist. The base of this composition is day of therapy showed significant reduction in size of very slightly soluble in water for better penetration of the traumatized area and almost absence of pain. On the drug in the affected areas. the fifth day of therapy the tissue returned to its pre EXAMPLE V extraction, normal size without any pain and the pa tients were dismissed. Each one Gram (1 Gm) of a cream composition con 25 in the foregoing examples, glycerin is used as a sweet tains: ening agent or vehicle in place of syrups (syrups are contraindicated in toothpastes due to their high carbo phenylephrine hydrochloride 10.00 mg .00 %, hydrate content increasing the incidence of tooth de diphenhydramine hydrochloride 5.00 mg 0.5 % benzocaine hydrochloride 100.00 mg 10.00 % cay) and to maintain the consistency of the toothpaste; tetracaine hydrochloride 10.00 mg 1.0 % propylene glycol is used in the formulation as a diluent oxyquinoline sulfate 10.50 mg 1.05 % menthol 4.80 mg 0.48 f and binder and may serve as a substitute for glycerin ichthanol 10.00 mg OO % and alcohol; methylparaben is used as a preservative zinc oxide 0.00 mg OO % due to its inhibitory action on the microorganisms; sac petrolatum, lanolin q. S. charine sodium solution is used as a sweetening agent; 35 pepermint oil is one of the many essential oils that can This cool, soothing, water insoluble cream composi be used as flavoring agents; mineral oil in this invention tion is intended for use as a topical applicant on the af. is used as a diluent, sodium lauryl sulfate is used as an fected areas. The patients are instructed to apply the emulsifier and foaming agent; dicalcium phosphate, cream on the affected areas two to four times daily, de due to its fineness is employed as an abrasive; sodium pending on the severity of the condition, or as recom 40 carboxymethylcellulose is used as an emulsifier and mended by the physician or dentist. Rinsing with water thickening and suspending agent; and distilled water in after use is discouraged for about 1 hour for better ab the context of this invention is used as a vehicle and sorption of the drug by the tissues. dilutant. EXAMPLE VI 45 EXAMPLE VII Each 90 cc (3 fl.oz.) of a toothpaste composition con A toothpaste was prepared as in Example VI with the tains: addition of the following ingredient: Stannous flouride 1 ppm (one part per million) phenylephrine hydrochloride 900.00 mg 1.00% Stannous flouride and other flouride derivatives such diphenhydramine hydrochloride 450.00 mg 0.5% as sodium flouride, monoflourophosphate, potassium benzocaine hydrochloride 4,500.00 mg 5.00% tetracaine hydrochloride 900.00 mg 1.00% flouride, etc. are effective anticariogenic substances glycerin (glycerol) 1,000.00 mg 1.10% used in toothpaste to control tooth decay by their ac propylene glycol 18,000.00 mg 19.80% mineral oil 1,000.00 mg 1.10% tion on the protein portion of the enamel and dentin peppermint oil 300.00 mg 0.33% making the said protein portions harder and subse saccharine sodium solution 50% 100.00 mg 1.10% 55 sodium lauryl sulfate 1,500.00 mg 1.65% quently more resistent to acid desolution and bacterial dicalcium phosphate (in fine powder) 54,000.00 mg 59.40% invasion. Such substances are generally used in concen sodium carboxymethylcellulose 120 H 900.00 mg t.00% methylparaben 100.00 mg 0.11% trations of 0.25 to 10 ppm. sodium thiosulfate 20.00 mg 0.02% Other preservatives and their concentrations that can distilled water qs. 90 cc. be used in lieu of methylparaben in the context of this invention are: This composition is intended to be used as a tooth paste. The patients are instructed to squeeze approxi sodium bisulfite 0.05 - 0.25 weight percent mately 1 inch of the toothpaste on a toothbrush and sodium benzoate 0.05 - 0.25 do. gently massage the affected areas as teeth are brushed sodium thiosulfate 0.01 - 0.20 do. for about 1 to 2 minutes, and expel the remainder with 65 chlorobutanol 0.01 - 1.0 do. outrinsing the mouth for about 1 hour. The procedure thinnerosal 0.00 - 0.01 do. should be repeated three to four times daily, depending phenylmercuric acetate 0.00 - 0.01 do. 3,832,460 19 20 The following substances are wetting and foaming severe nature or where more rapid reduction in size of agents which can be used to reduce the surface tension tissue is indicated. In that case typical application of of the mucous membrane to improve penetration of the the drug three times a day is suggested: in the morning, basic active ingredients. Except as noted, one or more at noon, and at bedtime. can be used in place of the sodium lauryl sulfate of Ex 5 The suggested dosage of the vasoconstrictor is be ample VI or as added ingredients in the formulations: tween 0.0125 percent and 5 percent and that of the an tihistamine ranges from one half to equal concentration benzalkonium chloride of the vasoconstrictor employed. The ratio of vasocon *benzethonium chloride strictor to antihistamine in a typical example of this in thonzonium bromide O vention is either 1:0.5 or 1:1. The concentration of an sulfocolaurate esthetic should be between 0.0125 percent and 20.0 dioctyl sodium sulfosuccinate percent by weight of the composition. sodium alkyl sulfoacetate The recommended dosages of the vasoconstrictors sodium lauryl sarcocinate are: *cetyl pyridinium chloride 15 sodium tetradecyl sulfate For adults and children over six years of age: *These compounds are preferably not used in same formulations with other soaps and detergents. They are cathionic surface active agents and in solution inactivate anionic surface active agents, for cxample Severe hypertrophy or enlargement soaps and detergents such as sodium lauryl sulfate. These compounds Fluid composition 0.5 - 2.5% are also mildly antiseptic and bacteriostatic. Hence, they can be used Paste composition 1.0 - 5.0% where a preservative is employed. 20 Mild to moderate hypertrophy or enlargement Fluid composition 0.125 - 0.5% The essential components of the toothpaste composi Paste composition 0.25 - O.75% tion of this invention are the alkaloid and the antihista Daily oral hygiene and prophylaxis mine each in a concentration of from about 0.0125 to Fluid composition .05 - 0.125% 5.0 weight percent, the anesthetic in an amount of from Paste composition 0.015 - 0.125% about 0.0125 to 20 weight percent, an alkaloid preser 25 vative in an amount from about 0.001 to 0.5 weight For children six years of age or younger: percent, a suspending agent in an amount of about 0.002 to 2.0 weight percent and from about 1 to 21 Severe hypertrophy or cnlargement Fluid composition 0.025 - 0.25% weight percent of a moisture retainer, with the balance Paste composition 0.05 - 0.25% of the composition being water. 30 Mild to moderate hypertrophy or cnlargement Suitable compounds for use as the alkaloid preserva Fluid composition 0.0125% - 0.025% Paste composition 0.025%, - 0.25% tive are methylparaben, propylparaben, sodium bisul Daily oral hygiene and prophylaxis fate, sodium benzoate, sodium thiosulfate, chlorobuta Not generally recommended nol, thimersol and phenylmercuric acetate. Preferred suspending agent materials are sodium carboxymethyl 35 These concentrations of the vasoconstrictor are only cellulose, methylcellulose, bentonite, acacia, sterculia by way of example and recommended dosage and do gum and tragacanth. Preferred moisture retainer mate not limit the percentage concentrations within the lim rials are glycerin, propylene glycol, sorbital, polyethyl its of the given examples. People knowledgeable in the ene glycol, diethylene glycol monoethyl ether, polysor arts of compounding pharmaceuticals may with few tri bate, monolaurate and polyoxyethylene sorbitan. 40 als arrive to a preferred concentration of the active in While the toothpaste composition of this invention gredients falling within the range of 0.0125 percent and need only employ the alkaloid, antihistamine, anes up to 5 percent. thetic preservative, suspending agent and moisture re The use of sympathominetic amines in combinations tainer components, excellent results have been ob with antihistaminic agents for treatment of hyperplastic tained from a more balanced toothpaste formulation 45 or hypertrophied and enlarged tissue has never been which included, in addition to the above components, suggested or implied before; the mode of action of this from about 0.01 to 0.5 weight percent of a sweetening combination is different than that obtained from either agent, about 0.01 to 1.5 of a foaming agent and about agent used alone. While the sympathomimetic amines 30 to 65 weight percent of an abrasive. have pharmacodynamic action on the chemoreceptors Examples of abrasive materials which can be used in 50 of the endothelial cells of the capillary membranes re this invention are pumice, calcium carbonate, stannic Sulting in a physiological antagonism of the effects of oxide, dibasic calcium phosphate, magnesium carbon the histamine on the effector cells, the antihistaminics ate and tribasic calcium phosphate. Suitable sweeten prevent the access of histamine to its receptor site in ers include sodium cyclamate, calcium cyclamate, sac the cells by competetive inhibition without causing a charines and sodium saccharine. Suitable foaming 55 cellular response or chemical reaction or antagonism agents include sodium lauryl sulfate, sodium tetradecyl. between the histamine and the antihistaminic agent. sulfate, sodium lauryl sarcocinate, dioctyl sodium sul Further, vasoconstrictor-antihistamine combination fosuccinate sulfocolaurate, thonzonium bromide, employed in this patent virtually eliminates any side ef methyl benzathonium chloride, dichlorobenzalkonium 60 fect produced by either agent used alone; the sedative chloride, dichlorobenzathonium chloride, and cetyl effect of the antihistaminic agent will counteract the pyridinum chloride. stimulant effect of the vasoconstrictor. Finally, I am not Because the vasoconstrictor-antihistamine aware of employing vasoconstrictor-antihistamine anesthetic combination of this invention has a long du combination in high acid or high alkaline pH as de ration of action, administration in the morning and at scribed herein due to the precipitation of the alkaloids bedtime is generally recommended. Some patients may 65 and the antihistamines, by the alkaline compounds; require treatment more frequently, especially where however, I have discovered that concentration of more hypertrophy or hyperplasia or tissue enlargement is of than 10 percent of alcohol or glycols such as glycerin 3,832,460 21 22 or propylene glycol, will prevent the said precipitation R in either the fluid or paste compositions. R1-COC)1- R. -N/ In addition to the foregoing, I am not aware of any N one suggesting or advocating a process or a composi R tion for the treatment of pain associated with hypertro phy or hyperplasia and oral tissue enlargement. Treat wherein R with its carbonyl group may be benzoic and ment of the pain symptom is just as important to the paramino benzoic acid or meta-amino benzoic acid, R2 comfort and the well being of the patient as is the treat is selected from the group consisting of aliphatic or aro ment of the condition itself. This invention deals not matic radicals having up to 14 carbon atoms each and only with the therapeutic treatment and the prevention () of oral tissue enlargement but it also relates to the Ra and R4 are selected from the group consisting of hy aleviation of the pain phenomena which is an important drogen and aliphatic or aromatic radicals having up to and integral part of the entire process of tissue differen 14 carbon atoms each, and said aminoacyl amides hav tiation and proliferation expected with this condition. ing the structure Needless to say, pain is the first symptom most patients 15 R afflicted with this condition will experience and the / need for its treatment is obvious. Topical anesthetics R-NH-COR-N used alone are not as effective in the treatment of pain associated with tissue enlargement as would two topical R anesthetics such as benzocaine and tetracaine com 20 bined with a sympathomimetic amine and a antihista wherein R is selected from xylene or toluene, R is se mine. Local anesthetic agents such as benzocaine and lected from the group consisting of aliphatic or aro tetracaine although are classified as anesthetic drugs matic radicals having up to 14 carbon atoms each and they are in their pharmacologic action analgesic since R8 and R are selected from hydrogen and aliphatic or by definition anesthesia is a state of depressed con 25 aromatic radicals having up to 14 carbon atoms each, sciousness with inhibition or abolishment of pain and said alkaloid and antihistaminic compounds each being analgesia is a state of inhibition and abolishment of present in said composition in an amount of from about pain without loss of consciousness when the drugs are 0.0125 to 5.0 per cent by weight of the composition, used systemically. Topical application of an anesthetic and said anesthetic component being present in an agent will produce insensitivity or insensibility to pain amount of from about 0.0125 to 20.0 per cent by in a circumscribed area without central nervous system weight of the composition. depression even when high concentrations of the drug 2. A composition according to claim 1 wherein said is employed, therefore the terms anesthesia and analge antihistaminic compound is selected from the group sia or anesthetic drug, or analgesic drug are used inter consisting of antazoline hydrochloride, diphenhydra changeably to indicate insensibility or abolishment to 35 mine hydrochloride thonzylamine hydrochloride, pain when these drugs are used topically on the oral tis chlorphenamine maleate, pyrilamine maleate, pheni Sc. ramine maleate and mixtures thereof. This invention has been described in detail with par 3. A composition according to claim 1 wherein said ticular reference to preferred embodiments thereof, anesthetic compound is selected from the group con but it will be understood that variations and modifica 40 sisting of benzocaine hydrochloride, tetracaine hydro tions can be effected within the spirit and scope of the chloride and mixtures thereof. invention. The disclosure therein is by way of example 4. A treatment for tissue which is hypertrophied or and included in the invention are all modifications and hyperplastic comprising applying to the area to be equivalents falling within the scope of the appended treated the composition of claim 1. claims. 45 5. A toothpaste composition according to claim 1 I claim: comprising said alkaloid, anesthetic and said antihista 1. A composition for the treatment of hypertrophied minic compounds, from about 0.001 to 0.5 percent of or hyperplastic oral tissue comprising (a) an alkaloid a preservative, from about 0.002 to 2.0 percent of a selected from the group consisting of aromatic amines suspending agent and from about 1 to 21 percent of a having between about 6 to 10 carbon atoms and ali 50 moisture retainer, the remainder of said composition phatic amines having between about 4 to 7 carbon being water and said percentages being based on the atoms, (b) an antihistaminic component selected from weight of the total composition. the group consisting of antazoline hydrochloride, tripe 6. A toothpaste composition according to claim 5 lennamine hydrochloride, tripelennamine citrate, thon wherein said suspending agent is selected from the zylamine hydrochloride, methapyriline hydrochloride, 55 group consisting of sodium carboxymethylcellulose, methapheniline hydrochloride, pyrilamine maleate, methylcellulose, bentonite, acacia, sterculia gum and chlorphenamine maleate, chlorothen, pheniramine, tragacanth, and wherein said moisture retainer is se pheniramine maleate, chlorocyclizine hydrochloride, lected from the group consisting of glycerin, propylene diphenhydramine hydrochloride, doxylamine succin glycol, sorbital, polyethylene glycol, diethylene glycol ate, phenyltoloxamine citrate, diphenylpyraline hydro monoethyl ether, polysorbate, monolourate and poly chloride, phenindamine tartrate, and thenyldiamine hy oxyethylene sorbitan. drochloride, and (c) an anesthetic component selected 7. A composition according to claim 1 further includ from the group consisting of secondary and tertiary ing from about 0.001 to 0.5 weight percent of a preser amino esters of aromatic acids and secondary and ter 65 vative selected from the group consisting of methylpar tiary aminoacyl amides of aromatic acids, said amino aben, propylparaben, sodium bisulfite, sodium benzo esters having the structure ate, sodium thiosulfate, chlorobutanol, themersoad and phenylmercuric acetate. 3,832,460 23 24 8. A mouthwash composition according to claim 7 shistaminic compound, anesthetic compound and pre comprising an aqueous solution of said alkaloid, anti servative in a suspending agent selected from the group histaminic compound, anesthetic compound and pre consisting of sodium carboxymethylcellulose, methyl servative. cellulose, bentonite acacia, sterculia gum and traga 9. A water soluble tablet composition according to 5 conth. claim 7 comprising a suspension of said alkaloid, anti ck k k is k

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