AU2485597A - Method of treatment for nasal and sinus dysfunction, and horseradish preparation therefor - Google Patents

Description

ms~ CBI-El~ P S F Ref: 278883D1

AUSTRALIA

PATENTS ACT 1990 FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant: Horseradish Spray, Inc.

6125 Clayton Avenue Suite 430 St. Louis Missouri 63117 UNITED STATES OF AMERICA r r r r s r Actual Inventor(s): Address for Service: Invention Title: William H. Friedman Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Method of Treatment for Nasal and Sinus Dysfunction, and Horseradish Preparation Therefor The following statement is a full description of this Invention, best method of performing it known to me/us:- Including the METHOD OF TREATMENT FOR NASAL AND SINUS DYSFUNCTION, AND HORSERADISH PREPARATION THEREFOR Field Of The Invention This invention relates to a method of treatment for nasal and sinus dysfunction comprising topically applying a horseradish, sinigrin or allyl isothiocyanate preparation to affected mucosa. The invention also relates to preparations for the treatment of nasal and sinus dysfunction, including preparations of horseradish, sinigrin and allyl isothiocyanate.

Background Of The Invention Many people suffer from nasal and sinus dysfunction.

Examples of nasal and sinus dysfunction include allergic and vasomotor inflammatory conditions of nasal mucous membranes, sinugenic headaches, post nasal discharge, and the like.

Nasal sprays have been used in the treatment of such nasal and sinus dysfunctions, but are not without drawbacks.

15 For instance, common nasal sprays containing sympatho-mimetic Scompounds, and over-the-counter remedies containing phenylephrine hydrochloride, oxymetazoline hydrochloride, or xylometazoline are generally considered to be harmful when used over long periods of time because they cause damage to nasal mucosal ciliary function, and they cause rebound mucosal thickening leading to nasal congestion. The manufacturers of certain over-the-counter remedies warn that their products should not be used for more than three days. Also, the use or abuse of these drugs has resulted in anosmia, prolonged nasal obstruction, and habituation of the medications.

-2- Other nasal sprays in the art include saline nasal sprays and topical steroid sprays. It is thought that the antiinflammatory effect of steroid sprays produces a beneficial reaction in the nasal and sinus mucosa. However, such sprays 3 can produce mucosal atrophy in post surgical states, and are generally effective only in reducing inflammation. They generally have inconsequential decongestant or physiological mucosal effects in mobilizing secretions or stimulating cells to evacuate secretions.

Another drawback of the prior art preparations is that a significant segment of the population is reluctant to apply artificial compositions to their nasal mucosa. As a result, S topical therapy for nasal and sinus dysfunction in this segment of the population is largely nonexistent.

1 Attempts have been made to produce natural remedies for certain ailments. For instance, Stammberger has administered capsaicin p (trans-8-methyl-N-vanillyl-6-nonenamide), the pungent extract of red pepper, to patients with headaches.

However, the capsaicin has been found to produce only profound vasodilation, sneezing, and either vasomotor or cholinergic secretory episodes. Also, the capsaicin is known to destroy unmyelinated C fibers of sensory and vagal afferent neurons.

Attempts have also been made to provide oral 2 horseradish remedies for certain ailments. Mays, U.S. Patent No. 98,875, relates to a medical compound for alleviating and curing asthma, coughs and colds. The compound includes pulverized horseradish. Diets, U.S. Patent No. 74,205 discloses a medical compound containing horseradish for the cure ll~rs~ ~--sRsPaasrprasllc -3of consumption. These oral horseradish remedies include substances, such as apple cider, ground ivy, and red beets, that are not suitable for topical applications.

Other natural oral remedies are known in the art.

S Reeves, U.S. Patent No. 28,904, relates to a treatment for inflammatory diseases of the pulmonary organ that includes the use of capsaicin or African cayenne pepper. Greene, U.S. Patent No. 378,504, relates to a catarrh treatment which includes red pepper (capsaicin).

However, none of the above-cited prior art provides a e topical therapy or a preparation which is consistently safe and effective in the treatment of most nasal and sinus dysfunctions.

Summary Of The Invention This invention provides an improved method of treatment for nasal and sinus dysfunction, and compositions therefor.

Broadly, the method of' treatment for nasal and sinus dysfunction comprises topically applying a therapeutic amount of S horseradish to affected mucosa. The horseradish may be dispersed in a dilute carrier solution. Preferably, the horseradish dispersion will be sprayed onto affected mucosa.

The horseradish may be suspended in a sodium chloride solution.

Another aspect of the present invention relates to a method of treatment for nasal and sinus dysfunction comprising topically applying a therapeutic amount of sinigrin to affected mucosa. The sinigrin may be applied in the form of a dilute carrier solution, and may be sprayed onto affected mucosa.

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-4- Another aspect of the present invention relates to a method of treatment for nasal and sinus dysfunction comprising topically applying a therapeutic amount of allyl isothiocyanate to affected mucosa. The allyl isothiocyanate may be applied in the form of a dilute carrier solution, and may be sprayed onto affected mucosa.

Another aspect of the present invention relates to a horseradish dispersion for the treatment of nasal or sinus dysfunction. The horseradish dispersion may comprise horseradish, sodium chloride, and water.

0 Another aspect of the present invention relates to a sinigrin solution for treating nasal or sinus dysfunction. The sinigrin solution may comprise sinigrin, sodium chloride, and water.

Another aspect of the present invention relates to an allyl isothiocyanate solution for treating nasal or sinus dysfunction. The allyl isothiocyanate solution may comprise allyl isothiocyanate, sodium chloride, and water.

Yet another aspect of the present inventionsrelates to 20 a method of making a horseradish dispersion useful in the treatment of nasal or sinus dysfunction. The method comprises reducing the size of the horseradish to form horseradish particles of about 100-1000 microns; dispersing the horseradish particles in a sodium chloride solution; filtering the dispersion to obtain a filtrate comprising horseradish particles with a mean particle diameter from 20-90 microns dispersed in the sodium chloride solution; and 1 ultrafiltering the filtrate to obtain a horseradish

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dispersion comprising horseradish particles having a mean particle diameter not greater than 20 microns; wherein the horseradish dispersion comprises from about 0.01 10.0 weight percent horseradish.

Detailed Description Of The Invention The present invention is useful in the treatment of a wide range of nasal and sinus dysfunctions. Such dysfunctions may occur prior or subsequent to surgery of the paranasal sinuses. Nasal and sinus dysfunctions may accompany allergic 10 and vasomotor inflammatory conditions of the nasal mucous membrane. Certain mucous membrane disorders are associated with sinugenic headaches, post nasal discharge, and mucous membrane disorders presumably related to an immotile cilia condition.

The latter condition results when the cilia of the mucous 15 membranes lining the nose (pseudo-stratified ciliated columnar epithelium) appear to perform their mucous clearance and secretional mobilization activities in a sluggish or incomplete fashion. Immotile cilia conditions are frequently found in patients with chronic sinusitis, allergy, asthma, and other systemic conditions in which the nose and sinuses play a major Srole.

Nasal and sinus dysfunctions are sometimes a result of limited mucosal contact within the nose, resulting from nasal septal deviations, middle turbinate "squeeze" syndromes, and other "trigger" type situations that produce long-standing headaches, often projecting to remote dermatromes of the head and neck.

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-6- Other types of nasal and sinus dysfunctions that may be treated according to the present invention include nasal congestion from allergic, vasomotor, or infectious etiologies, and crusting or atrophic rhinitides associated with infection or S surgery.

The preparations of the present invention may. vary widely in composition, however they will typically comprise horseradish, sinigrin, allyl isothiocyanate, or mixtures thereof, in a saline solution.

Topical applications may be performed by a number of techniques. A preparation may be sprayed onto the affected mucosa, or the nasal mucosa may be bathed with drops of the preparation. A preparation may be applied by loading the S preparation onto a swab and dabbing the swab on affected mucosa.

A preparation may also be applied as a nasal douche.

The preparations of the present invention preferably are derived from natural sources, although chemical synthesis of the active ingredients may also be employed. Horseradish (r-ohanus rusticanus) is the root of radicula armoracia. It 20 contains ascorbic acid and sinigrin. Black mustard (also referred to as brown mustard and red mustard) is derived from dried ripe seeds of brassica niqra. Its constituents include sinigrin, myosin, sinapine, sulfocyanate and fixed oil (erucic, behenic and sinapolic acids.) Sinigrin (l-thio-3-D-glucopyranose l-(N-(sulfo-oxy)-3butenimidate)) monopotassium salt can be isolated from black mustard seeds and from horseradish. It is commercially available under catalogue number 5-330-5 sold by Aldrich

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Chemical compoany, inc natural sources such yields allyl isothioc mv',rosinase, the latta2 is :reeiy soilube fcrmula: -Sinigrin preferably is derived from as horseradish or black mustard. SiniJarin vanate on hydrolysis with peroxidase or rbeina an enzvme found in black mustard.

in -,ater, and has t'-e folicwing c'nenica 1

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H OR A 2 Allyi isothiocvaflate (3-Isothiocyanatc-1-rcmene) is commercially available under cataloque number z3,320-5 sold by Aldrich Chemical Company, inc. Preferably it is derived from natural sources such as horseradish, black mustard, or caboace.

It can also be prepared from allyl iodide and potassium thiocyanate. Allyl isothiocyanate is of particular interest because it is considered to be the active moiety of horseradish.

It has been de';cribed as the volatile oil of mustard (Clinical Toxicoloav of Comecial Products, Williams and Wilkins, reference 1359, Fifth Edition 1985). Ally! isothiocyanate has been used as a counter-irritant in medicine, as a funoaiOci, as an insecticidal fumigant, and as a repellent for cats and dogs.

it is included in some model airplane cements at concentra=tions of 0.25-0.5% to deter "glue sniffing." it is a violent irritant unless either diluted or in its natural conjugated form, as in horseradish. It is used externally as a rubefacient (0.1 to 0.2% in 50% methanol). Allyl isothiocyanate is slightly soluble in waterF and has the following formula:

CH,=CHCHNCS

Irira gB~eP~C r~I~i~aa4 rrr.

Although the mode of operation of the present invention is not fully understood, it is believed that the beneficial effect of the preparations of the present invention may result from stimulating a focal physiological cellular S response in mucosa. A natural antibiotic effect may result when either sinigrin or allyl isothiocyanate, perhaps in combination ;ith ascorbic acid (vitamin is applied to affected mucosa.

Vitamin C is present in large concentrations in horseradish.

The concentration cf horseradish in the dispersion may vary. The concentration should be such that the user's nucosa do not become irritated, and generally is from about 0.01-10.0 weight percent horseradish. A preferred concentration is from about 3.0-10.0 weight percent, and a more preferred concentration is from about 8.0-10.0 weight percent horseradish.

The mean particle diameter of the horseradish should be small enough so that the user's mucosa do not become irritated, typically not in excess of 20 microns. A preferred mean particle diameter is from about 2 10 microns.

The concentration of sinigrin in the sinigrin soluticn O may vary. The concentration should be such that the user's mucosa do not become irritated, and generally is from about 4 0.01-10.0 weight percent sinigrin. A preferred concentration is Sfrom about 5.0-10.0 weight percent, and a more preferred concentration is from about 8.0-10.0 weight percent sinigrin.

The concentration of allyl isothiocyanate in the allyl isothiocyanate solution may vary. The concentration should be such that the user's mucosa do not become irritated, generally from about 0.01-2.0 weight percent allyl isothiocyanate.

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Preferred concentration is from about 0.05-2.0 weight vercent, adaore preferred concentration is from about 0.05-1.5 weight, vercert allyl isothiovanfate.

U The oH of the horseradishl, sinigrin, and allyl i sothnJocvaflte preparati-ons should be such that the user's mucosa do not become irr-t-ated. -A preferred vH is from about 4 7, and especially preferred is a pH of from about 6-7.

Sodium chloride in aaueous solution may desirably be present in the preparations of the present invention. The S 10 sodium chloride will generally be present in concentrations about 0.5-0.8% by weight, preferably from about and especially pre-ferably about 0.65'- weiaht percent sodium chloride. Other salts may optionally be utilized, such as potassium salts and/or magnesium salts.

151 The preparations; of the oresent invention will 9 -nerally be applied 'Periodically as necessary to treat nasal and sinus dysfunctions. About 2-1-0 m! of 0.01-10.0 weight Dercent horseradish or sainigrifl preparation may be applied to S affected mucosa every three hours. Preferably, about 5-10 nl of zO 8-1 weigh percnt horseradish will be applied once every 61 hours. About 2-10 ml of 0.01-2.0 -w eiaht percent allyl isothiocyarate solution may be applied to affected m~ucosa every *3 hours. Preferably, about 5-10 =1 of 1-0-2.0 w=eigt, perceintallyl isothiocyanate will be applied once every 6-12 hours.

The method of making the horseradish solution includes ultrafiltering a combination of horseradish and saline solution- Ultrafilterilg may be performed by a variety of technicques, such _7 as with medium porous Fisher filter paper having a 5 to micron retention rating; a Gelmnan membrane filter with a thick, nominal rating and a retentlion rating of 2 microns; or a Whatman filter number 40 having an 8 micron retention ratina.

The nrenarations of the oresent invention may contain activa or inert in=-arent-s. 'cr itanc=e, as'-o'-bc azid ma r resent. Ascorbic acid is benefiial because of its salutary effrects on muccus membranes, and it may be Dr-esent in concentrations of fr-oh about Drefer-ably from about 0.01-5.0%, and especially oreterahly from about by weight'. A buffer may be nresent. Preservatives such as ethyl alcohol may also be present.

Clinical Tests Horseradish sorays were oroduced and clinically tested on patients having a wide range of nasal and sinus dysfunctions.

Batches of horseradish spray were prepared as described below: Horseradish was first reduced in size to about 100-1000 microns- 270 ar-ams were mlaced in a steel beaker withn 1500 cc of 0.6t sodium chloride solution (aqueous) Ethyl alcohol was then added in such amounts that the resulting Qisioersion contained eithear 0.025., 0.03% or 0.04% ethyl al~ohol by weight-.

4 The mixtures wer then mechanically shaken for one minute and filtered throuch a number 20 wire mesh. They were then ultra filtered throuch medium filter paper and Diaced in sterile Diastia spray bottles. The mean oarticle diameter of the horseradish oartidles in the disper-sions was approximately microns. The resulting dispersions contained horseradish in concentrations of from about 8.0-10.0 Dercent by weiz=ht- -11- The horseradish dispersions were prescribed to 100 patients with postoperative healing mucous membrane states, allergic rhinitis, vasomotor rhinitis, sinugenic headache syndromes, and other inflammatory mucosal disease states.

Patients who had failures of other forms of therapy, or who had undergone sinus or nasal surgery were utilized in the study after being informed that the method and spray were experimental and should not be considered their primary mode of therapy. The prescribed rate of topical application was twice daily in each S 10 nostril. The dispersions were applied by spraying approximately ml of the dispersion onto affected mucosa.

Ninety-five percent of the treated patients showed good to excellent results from the treatment. Results were measured in terms of mobilization of crusts following surgery, accelerated postoperative healing following nasal and sinus S" surgeries, relief of congestion with improvement in inflammation in patients in vasomotor and allergic states and in patients with the common cold.

.One patient reported a return of his sense of smell after 15 years and multiple surgeries. Most patients reported improvement in their nasal airway, freedom from crusting and moderate to marked relief of sinusitis-induced headaches.

In some of the patients, two or more dysfunctional categories had coexisted. These included combinations of postoperative healing states, sinugenic headaches, vasomotor rhinitis, nasal congestion, crushing rhinitis, and allergic rhinitis. In many cases, all of the dysfunctional categories in these patients were alleviated.

n y -12- There were no instances of toxicity, or interference with other forms of therapy. No undesirable side effects were exhibited, such as degradation of nasal mucous membranes or worsening of nasal or sinus conditions. No hypersensitivity or allergic reactions were noted. Only five patients reported no imorovement in symptoms.

Variations and modifications of the present invention will be apparent to those skilled in the art. For example, the preparations may contain vitamins other than vitamin C. The following claims are intended to cover all such variations and modifications falling within the spirit and scope of the invention.

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Claims (19)

1. A method of treatment for nasal and sinus Sdysfunction comprising topically applying horseradish to affected mucosa.

2. The method of Claim 1, wherein the horseradish is dispersed in a carrier solution and the dispersion is sprayed onto affected mucosa,

3. The method of Claim 3, wherein the horseradish dispersion comprises from about 0.01-10.0 weight percent horseradish, and from about 0.50-0.70 weight percent sodium chloride.

The method of Claim 3, wherein the horseradish dispersion contains horseradish particles with a mean particle diameter not greater than 20 microns.

5. A method of treatment for nasal and sinus Sdysfunction comprising topically applying sinigrin to affected mucosa.

6. The method of Claim 5, wherein the sinigrin is S dissolved in a carrier solution and the solution is sprayed onto '20 affected mucosa.

7. The method of Claim 6, wherein the sinigrin solution comprises from about 0.01-10.0 weight percent sinigrin, and from about 0.50-0.70 weight percent sodium chloride.

8. A method of treatment for nasal and sinus dysfunction comprising topically applying allyl isothiocyanate to affected mucosa. *I i. Ice I i! -14-

9. The method of Claim 8, wherein the allyl isothiocyanate is dissolved in a carrier solution and the solution is sprayed onto affected mucosa.

The method of Claim 9, wherein the allyl isothiocyanate solution comprises from about 0.01-2.0 weight percent allyl isothiocyanate, and from about 0.50-0.70 weight percent sodium chloride.

11. A horseradish dispersion for the treatment of nasal or sinus dysfunction, the horseradish dispersion [0 comprising horseradish, sodium chloride, and water, wherein the concentration of horseradish is from about 0.01-10.0 weight percent of the dispersion.

12. The dispersion of Claim 11 comprising from about 0.01-10.00 weight percent horseradish, and from about 0.50-0.70 weight percent sodium chloride.

13. The dispersion of Claim 12, wherein the dispersion contains horseradish particles with a mean particle diameter not greater than about 20 microns.

14. A sinigrin solution for treating nasal or sinus dysfunction, the sinigrin solution comprising sinigrin and water, wherein the solution comprises from about 0.01-10.0 weight percent sinigrin.

The solution of Claim 14 comprising from about 10 weight percent sinigrin, and from about 0.50-0.70 weight percent sodium chloride.

16.- The solution of Claim 15, wherein the sinigrin is derived from horseradish or black mustard.

17. An allyl isothiocyanate solution for treating nasal or sinus dysfunction, the allyl isothiocyanate solution comprising allyl isothiocyanate and water, wherein the solution comprises from about 0.01-2.0 weight percent allyl isothiocyanate.

18. The solution of Claim 17 comprising from about 0.05-2.0 weight percent allyl isothiocyanate, and from about 0.50-0.70 weight percent sodium chloride.

19. The solution of Claim 18, wherein the allyl isothiocyanate is derived from horseradish or black mustard. A method of making a horseradish dispersion useful in the treatment of nasal or sinus dysfunction, the 1 method comprising: reducing the size of the horseradish to form 15 horseradish particles of about 100-1000 microns; dispersing the horseradish particles in a sodium chloride solution; filtering the dispersion to obtain a filtrate comprising horseradish particles with a mean particle diameter of from 20-90 microns dispersed in the sodium chloride solution; and ultrafiltering the filtrate to obtain a horseradish dispersion comprising horseradish particles having a mean particle diameter not greater than 10 microns; wherein the horseradish dispersion containing from about 0.01 10.0 weight percent horseradish. e DATED this TWELFTH day of JUNE 1997 Horseradish Spray, Inc. Patent Attorneys for the Applicant SPRUSON FERGUSON war