AU678561B2 - Pharmaceutical compositions and methods for treating cold symptoms - Google Patents

Description

an q 9307 9 PCT ANNOUNCEMENT OF THE LATER PUBUCATION OF INTERNATIONAL SEARCH REPORTS INTERNATIONAL APPLICATION PUBLISHED UNUIzK inn rn I ,ir .tATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 94/08551 A61K 47/10, 9/00 A3 (43) International Publication Date: 28 April 1994 (28.04.94) (21) International Application Number: PCT/US93/08887 (74) Agents: REED, David et al.; The Procter Gamble Company, 5299 Spring Grove Avenue, Cincinnati, OH (22) International Filing Date: 22 September 1993 (22.09.93) 45217 (US).

Priority data: (81) Designated States: AU, CA, FI, JP, KR, NO, NZ, RU, Eu- 07/955,013 9 October 1992 (09.10.92) US ropean patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).

(71)Applicant: THE PROCTER GAMBLE COMPANY [US/US]; One Procter Gamble Plaza, Cincinnati, OH Published 45202 With international search report.

Before the expiration of the time limit for amending the (72) Inventors: UPSON, James, Grigg 11268 Springfield Pike, claims and to be republished in the event of the receipt of Springdale, OH 45246 RUSSELL, Carmelita, amendments.

Macklin 607 Vincennes Court, Cincinnati, OH 45231 (88) Date of publication of the international search report: 23 June 1994 (23.06.94) 67856 (54)Title: PHARMACEUTICAL COMPOSITIONS AND METHODS FOR TREATING COLD SYMPTOMS (57) Abstract Pharmaceutical compositions comprising a safe and effective amount of at least one pharmaceutical cold active; 3-1-menthoxy propane 1,2-diol; and a pharmaceutically-acceptable carrier material suitable for oral or nasal administration. The present invention also includes methods for treating cough, cold, cold-like, allergy and/or flu symptoms in a human or lower animal, said method comprising administering to a human or lower animal in need of such treatment, by oral or nasal administration, a composition comprising 3-1-menthoxy propane 1,2-diol.

WO 94/08551 PCrT/US93/08887 -1- PHARMACEUTICAL COMPOSITIONS AND METHODS FOR TREATING COLD SYMPTOMS BACKGROUND OF THE INVENTION The present invention relates to orally or nasally administrable pharmaceutical compositions comprising at least one pharmaceutical active, 3--menthoxy propane 1,2-diol (herein referred to as "MPD") and pharmaceutically-acceptable carrier material(s). The present invention also relates to methods for treating cough, cold, cold-like, allergy and/or flu symptoms in a human or lower animal by administering, orally or nasally, a composition comprising MPD.

Pharmaceutical compositions safe and effective for treating colds, flu, and allergies are well known. Over-the-counter medications provide symptomatic relief of such illnesses. Typical symptoms of the common cold are mild malaise, sore throat and nasal complaints.

Nasal discharge, nasal congestion and/or sneezing frequently are present. Also common are sore, dry or scratchy throat and hoarseness and couga. Other symptoms may include mild burning of the eyes, loss of smell and taste, a feeling of pressure or fullness in the sinuses or ears, headache, and vocal impairment. Flu symptoms are similar but usually of greater severity, including fever, generalized aches and pains, fatigue and weakness, and chest discomfort. Allergy symptoms are more akin to the common cold, with more frequent/severe sinus pressure, drainage and headaches.

Prior art formulations for treating cough, cold, cold-like, allergy and/or flu symptoms and the discomfort, pain, fever and general malb e associated therewith typically contain one or more of the pharmaceutical actives which are analgesics, anesthetics, antihistamines, decongestants, cough suppressants, antitussives and expectorants.

It is an object of the present invention to provide compositions and methods useful for treating cough, cold, cold-like, allergy and flu symptoms in humans and lower animals in need of such treatment.

Another object is to provide such compositions and methods having increased perceived efficacy, speed of relief and/or duration of relief, and/or improved aesthetics.

These and other objects of the present invention will become la readily apparent from the detailed description which follows.

All percentages and ratios used herein are by weight, and all measurements are made at 25 0 C, unless otherwise specified.

SUMMARY OF THE INVENTION The present invention is directed to pharmaceutical compositions comprising: a safe and effective amount of at least one pharmaceutical cold active; 3-1-menthoxy propane 1,2-diol; and a pharmaceutically-acceptable carrier material suitable for oral or nasal administration.

The present invention is also directed to methods for treating cough, cold, cold-like, allergy, and flu symptoms in a human or lower animal, said method comprising administering to a human or lower animal in need of such treatment, by oral or nasal administration, a composition comprising 3-1-menthoxy propane 1,2-diol.

Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives or components or integers.

o o o *ooo* Ep c*WN RDE.N EIL 379.O WO 94/08551 PCT/US93/08887 -2 readily apparent from the detailed description which follows./ All percentages and ratios used herein are by wejgtit, and all measurements are made at 25'C, unless otherwise specjffed.

SUMMARY OF THE INVENTION The present invention is directed to pharmaceutical compositions comprising: a safe and effective amount of at least one pharmaceutical cold active; 3-1-men hoxy propane 1,2-diol; and a pharmaceutically-acceptable ca ier material suitable for oral or nasal administration.

The present inve on is also directed to methods for treating cough, cold, cold- ke, allergy, and flu symptoms in a human or lower animal, said ethod comprising administering to a human or lower animal i eed of such treatment, by oral or nasal administration, a comp _stion comprising 3-1-menthoxy propane 1,2-diol.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical compositions comprising: at least one pharmaceutical cold active; 3-1menthoxy propane 1,2-diol and pharmaceutically-acceptable carrier material suitable for oral or nasal administration. The components of the compositions according to the present invention, and representative amounts, as well as the present invention methods are described in detail as follows.

Pharmaceutical Cold Actives: The pharmaceutical compositions according to the present invention comprise pharmaceutical cold actives useful for treating cough, cold, cold-like, allergy and/or flu symptoms. Such pharmaceutical actives are well known, and are generally recognized as being an active having analgesic, anti-inflammatory, anesthetic, antihistamine, decongestant, cough suppressant, demulcents, antitussive, and/or expectorant properties.

The compositions of this invention therefore contain one or more known pharmaceutical cold actives, particularly those commonly utilized in cough/cold preparations, such as, for example, a decongestant such as pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, their pharmaceutically acceptable salts; an antitussive such as dextromethorphan, chlophedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, menthol, hydrocodone, hydromorphone, fominoben, their pharmaceutically-acceptable salts; an expec-

I

WO 94/08551 PCT/US93/08887 3 torant or mucolytic such as glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their pharmaceutically acceptable salts; and an antihistamine such as chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine, azatadine, doxylamine, tripelennamine, cyproheptadine, hydroxyzine, clemastine, carbinoxamine, phenindamine, bromodiphenhydramine, pyrilamine, their pharmaceutically acceptable salts, as well as the non-sedating antihistamines which include acrivastine, AHr-11325, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodcxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, their pharmaceutically acceptable salts: all of these components, as well as their acceptable dosage ranges are described in the following: U.S. Patent 4,783,465 to Sunshine et al., issued November 8, 1988, U.S. Patent 4,619,934 to Sunshine et al., issued October 28, 1986, which are incorporated by reference herein. Also useful are bronchodilators such as terbutaline, atropine, aminophylline, epinephrine, isoprenaline, metaproterenol, bitoterol, theophylline and albuterol.

Also used are analgesic compounds such as aspirin, acetaminophen, ibuprofen, and naproxen; and topical anesthetics/analgesics such as phenol, benzocaine, hexyl resorcinol, and dyclonine.

The compositions of the present invention comprise a safe and effective amount of at least one pharmaceutical cold active. The phrase "safe and effective amount", as used herein, means an amount of a compound or composition high enough when administered orally or nasally to significantly positively modify the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of the pharmaceutical cold active will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific pharmaceutical cold active employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician. Typically, the pharmaceutical cold active(s) comprise from about 0.001% to about 99.9%, by weight, of the pharmaceutical compositions of the present invention, preferably from about 0.001% to about 75%, and most prefer- WO 94/08551 PCT/US93/08887 -4ably from about 0.01% to about 3-1-Menthoxy Propane 1,2-Diol: The pharmaceutical compositions of the present invention also comprise 3-1-menthoxy propane 1,2-diol This material is described in detail in U.S. Patent 4,459,425, issued July 10, 1984 to Amano et. al, incorporated herein by reference in its-entirety. While not to be limited by theory, it is believed that the benefits obtained by the use of MPD in the compositions of the present invention are the result of the unique cooling profile for this compound. MPD is commercially available, being sold by Takasago Perfumery Co., Ltd., Tokyo, Japan.

MPD typically comprises from about 0.001% to about 10% by weight of the pharmaceutical compositions of the p.,esent invention, preferably from about 0.01% to about and most preferably from about 0.01% to about Pharmaceutically-Acceptable Carrier Material: The term "pharmaceutically-acceptable carrier materials" as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for oral and/or nasal administration to a human or lower animal. The term "compatible", as used herein, means that the components of the compositions of the present invention are capable of being commingled with the pharmaceutical cold active, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the compositions under ordinary use situations. Pharmaceutically-acceptable carrier materials must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human being treated.

The choice of pharmaceutically-acceptable carrier materials to be used in conjunction with the pharmaceutical cold active of the present compositions is basically determined by the dose form for the compositions. The preferred dosage forms are liquid solutions, liquid suspensions, tablets, capsules and the like, comprising a safe and effective amount of the pharmaceutical actives. Pharmaceuticallyacceptable carrier materials suitable for the preparation of dosage forms for oral and nasal nasal sprays) administration are well-known in the art. Their selection will depend on secondary considerations like taste, cost, shelf stability, which are not WO 94/08551 PC/US93/08887 critical for the purposes of the present invention, and can be made without difficulty by a person skilled in the art. Preferably the present invention compositions comprise from about 0.1% to about 99.99% of one or more pharmaceutically-acceptable carrier materials.

Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules, lozenges and bulk powders and liquid forms such as syrups and suspensions. These oral forms comprise a safe and effective amount of the pharmaceutical cold active component.

Solid oral dosage forms preferably contain from about 0.1% to about 99%, more preferably from about 25% to about 99%, and most preferably from about 50% to about 99% of the pharmaceutical cold active component. Liquid oral dosage forms preferably contain from about 0.001% to about 25% and more preferably from about 0.001% to about 10% and most preferably from about 0.01% to about 5% of the pharmaceutical cold active component.

Tablets can be compressed, molded, triturated, enteric-coated, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives and flow-inducing agents. Also useful are soft gelatin capsules.

Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics, Vol. 7, (Banker and Rhodes, editors), 359-427 (1979), incorporated by reference herein. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are described in Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (1980), incorporated herein by reference.

Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, pseudo emulsions, suspensions, and solutions and/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, coloring agents, and flavoring agents.

Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms, are described* in U.S. Patent 3,903,297, Robert, issued September 2, 1975, incorporated by reference herein. Although water itself may make up the entire carrier, typical liquid formulations preferably contain a co-solvent, for example, propylene glycol, polyethylene glycol, WO 94/08551 PCFUS93/08887 6 alcohol, glycerin, sorbitol solution and the like, to assist solubilization and incorporation of water-insoluble ingredients, such as flavoring oils and the like into the composition.

Other optional ingredients well known to the pharmacist's art may also be included in amounts generally known for these ingredients, for example, natural or artificial sweeteners, flavoring agents, colorants and the like to provide a palatable and pleasant looking final product, antioxidants, for example, butylated hydroxy anisole or butylated hydroxy toluene, and preservatives, for example, methyl or propyl paraben, potassium sorbate, or sodium benzoate, to prolong and enhance shalf life. A preferred optional component is also materials other than MPD having cooling properties, such as menthol and menthol-like compounds such as N-ethyl-p-menthane-3-carboxamide (preferably at from about 0.001% to about more preferably from about 0.001% to about and mixtures thereof. A preferred optional component is also caffeine.

Method of Treatment: The present invention also relates to a method for treating cough, cold, cold-like, allergy and flu symptoms in a human or lower animal. Said method comprises administering to a human or lower animal in need of such treatment, by oral or nasal administration, a composition comprising MPD. Preferred pharmaceutical compositions for administration acccrding to the present invention method comprise from about 0.001% to about 10% (preferably from about 0.01% to about of MPD, and from about 0.1% to about 99.999% (preferably from about about 99.99%) of-pharmaceutically-acceptable carrier material(s). Preferred is administering, either orally or nasally, a safe and effective amount of a composition according to the present invention. Most preferred is oral administration.

The following examples further describe and demonstrate embodiments within the scope of the present invention. These examples are given solely for the purpose of illustration and are not to be construed as a limitation of the present invention as many variations thereof are possible without departing from the spirit and scope.

Example 1 Cough Syrup Ingredient Amount/15m1 dose Dextromethorphan HBr 20 mg Glyceryl Guaiacolate 200 mg WO 94/08551 PCT/US93/08887 7 Sucrose 8.16 grams Alcohol 1 ml .Citric Acid, Anydrous 4 mg Sodium Citrate 300 mg

MPD

1 15 mg WS-3 2 0.75 mg Menthol 7.5 mg Coloring Agent 4.5 mg Water, Purified Q.S. to 15 ml 1) 3-1-menthoxy propane 1, 2-diol, supplied by Takasago Perfumery Co., Ltd., Tokyo, Japan 2) N-ethyl-p-menthane-3-carboxamide, supplied by Sterling Drugs This composition is prepared.by first dissolving the dextromethorphan and glyceryl guaiacolate in alcohol and then adding with constant mixing the menthol, MPD and WS-3. In separate containers dissolve the sucrose in a small portion of the water, dissolve the coloring agent in a separate small portion of the water, and in still another container dissolve the sodium citrate and citric acid in a small portion of the water. Finally, all the premixes and the remaining water are mixed with constant mixing to prepare a composition of the present invention having 20 mg of dextromethorphan and 200 mg of glyceryl guaiacolate per 15 ml of composition.

Administration (by drinking 15 ml) of this composition to a human patient having a cough associated with the common cold provides rapid, long-lasting relief of the cough in said human patient.

Example 2 Cough Drop Composition Ingredient W/W) Menthol, Natural 0.2211 Eucalyptus Oil 0.1455 MPD 0.0700 WS-3 0.0300 FD&C Blue #1 0.0022 Sugar

QS*

Low DE Corn Syrup QS* *60/40 Sugar/Low DE Corn Syrup (before cook); candy base used.

WO 94/08551 PCT/US93/08887 -8- This composition is prepared by standard drop forming techniques.

Administration (by sucking) of drops to a human patient having a cough. associated with the common cold provides rapid, long lasting relief of the cough in said human patient.

Claims (12)

1. A pharmaceutical composition comprising: a safe and effective amount of at least one pharmaceutical cold active;

3-1-menthoxy propane-1,2-diol; and pharmaceutically-acceptable carrier material suitable for oral or nasal administration. 2. The pharmaceutical composition according to Claim 1 wherein the pharmaceutical cold active is selected from the group consisting of analgesics, anti-inflammatories, anesthetics, antihistamines, decongestants, cough suppressants, demulcents, antitussives, expectorants, and mixtures thereof. 3. The pharmaceutical composition according to Claim 2 wherein the .o pharmaceutical cold active is selected from the group consisting S• of pseudoephedrine, phenylpropanolamine, phenylephrine, ephe- drine, dextromethorphan, cnlophedianol, carbetapentane, carami- 5 phen, noscapine, diphenhydramine, codeine, menthol, hydrocodone, hydromorphone, fominoben, glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbrom- phreniramire, triprolidine, azatadine, doxylamine, tripelen- :i0 namine. cyproheptadine, hydroxyzine, clemastine, carbinoxamine, phenindamine, bromodiphenhydramine, pyrilamine, acrivastine, AHR- 11325, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, terfenadine, terbutaline, atropine, aminophylline, epinephrine, isoprenaline, metaproter- enol, bitoterol, theophylline, albuterol, aspirin, acetaminophen, ibuprofen, naproxen, phenol, benzocaine, hexyl resorcinol, dyclonine, the pharmaceutically acceptable salts thereof, and mixtures thereof.

4. The pharmaceutical composition according to Claim 1 comprising from about 0.001% to about 10% of 3,1-menthoxy propane 1,2-diol. A pharmaceutical composition comprising: from about 0.001% to about 99.9% of at least one pharmaceu- 10 tical cold active; from about 0.001% to about 10% of 3-1-menthoxy propane 1,2-diol; and from about 0.1% to about 99.99% of pharmaceutically- acceptable carrier material suitable for oral or nasal administration.

6. The pharmaceutical composition according to Claim 5 wherein the pharma~?.utical cold active is selected from the group consisting of analgesics, anti-inflammatories, anesthetics, antihistamines, decongestants, cough suppressants, demulcents, antitussives, expectorants, and mixtures thereof. 9

7. The pharmaceutical composition according to Claim 6 wherein the pharmaceutical cold active is selected from the group consisting of pseudoephedrine, phenylpropanolamine, phenylephrine, ephe- drine, dextromethorphan, chlophedianol, carbetapentane, carami- 5 phen, noscapine, diphenhydramine, codeine, menthol, hydrocodone, hydromorphone, fominoben, glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbrom- phreniramine, triprolidine, azatadine, doxylamine, tripelen- 10 namine, cyproheptadine, hydroxyzine, clemastine, carbinoxamine, phenindamine, bromodiphenhydramine, pyrilamine, acrivastine, AHR- 11325, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, terfenadine, terbutaline, 00 15 atropine, aminophylline, epinephrine, isoprenaline, metaproter- enol, bitoterol, theophylline, albuterol, aspirin, acetaminophen, ibuprofen, naproxen, phenol, benzocaine, hexyl resorcinol, dyclonine, the pharmaceutically acceptable salts thereof, and mixtures thereof.

8. The pharmaceutical composition according to Claim 5 further comprising a material in addition to 3-1-menthoxy propane 1,2- diol having cooling properties.

9. The pharmaceutical composition according to Claim 8 wherein the I 11 additional material having cooling properties is selected from menthol, N-ethyl-p-menthane-3-carboxamide, and mixtures thereof. A pharmaceutical composition comprisina: from about 0.01% to about 30% of at least one pharmaceutical cold active; from about 0.01% to about 0.5% 3-1-menthoxy propane 1,2- diol; and from about 70% to about 99.99% of pharmaceutically accep- table carrier material suitable for oral or nasal adminis- tration.

11. The pharmaceutical composition according to Claim 10 wherein the pharmaceutical cold active is selected from the group consisting of analgesics, anti-infla.matories, anesthetics, antihistamines, *decongestants, cough suppressants, demulcents, antitussives, 5 expectorants, and mixtures thereof.

12. The pharmaceutical composition according to Claim 11 wherein the pharmaceutical cold active is selected from the group consisting of pseudoephedrine, phenylpropanolamine, phenylephrine, ephe- drine, dextromethorphan, chlophedianol, carbetapentane, carami- phen, noscapine, diphenhydramine, codeine, menthol, hydrocodone, **hydromorphone, fominoben, glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbrom- *phreniramine, triprol i dine, azatadine, doxylamine, tripelen- namine, cyproheptadine, hydroxyzine, clemastine, carbinoxamine, phenindamine, bromodiphenhydramine, pyrilamine, acrivastine, AHR- 11325, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, terfenadine, terbutaline, atropine, aminophylline, epinephrine, isoprenaline, metaproter- enol, bitoterol, theophylline, albuterol, aspirin, acetaminophen, ibuprofen, naproxen, phenol, benzocaine, hexyl resorcinol, dyclonine, the pharmaceutically acceptable salts thereof, and mixtures thereof. 12

13. The pharmaceutical composition according to Claim 10 further comprising from about 0.001% to about 5% of N-ethyl-p-menthane- 3-carboxamide.

14. A method for treating cough, cold, cold-like, allergy, and flu symptoms in a human or lower animal, said method comprising administering to a human or .ower animal in need of such treat- ment, by oral or nasal administration, a composition comprising 3-1-menthoxy propane 1,2-diol. The method according to Claim 14 whereby the composition admin- istered orally or nasally comprises from about 0.001% to about 10% of 3-1-menthoxy propane 1,2-diol and from about 0.1% to about

99.999% of pharmaceutically-acceptable carrier material. gS 16. The method according to Claim 15 wherein the composition admin- istered orally or nasally further comprises a safe and effective amount of at least one pharmaceutical cold active. 17. A method for treating cough, cold, cold-like, allergy, and flu symptoms in a human or lower animal, said method comprising administering to a human or lower animal in need of such treat- ment, by oral or nasal administration, a composition according to Claim 1. go 18. A method for treating cough, cold, cold-like, allergy, and flu symptoms in a human or lower animal, said method comprising administering to a human or lower animal in need of such treat- ment, by oral or nasal administration, a composition according to Claim 19. A method for treating cough, cold, cold-like, allergy, and flu symptoms in a human or lower animal, said method comprising administering to a human or lower animal in need of such treat- ment, by oral or nasal administration, a composition according to Claim A method for treating cough, cold, cold-like, allergy, and flu 13 symptoms in a human or lower animal, said method comprising administering to a human or lower animal in need of such treatment, by oral or nasal administration a composition according to claim 13. 21. A pharmaceutical composition according to claim 1 substantially as herein described with reference to any one of the examples. DATED: 8 April, 1997 PHILLPS ORMONDE FITZPATRICK Attorneys for: a dw 9..t THE PROCTER GAMBLE COMPANY *e* *ee EP C-.NUNWORDELLESPECIRLW93D7-3.DO IN I LRNA I1UNAL bbAKCH 1-WPUI Intenf Wa Application No PCT/IJS 93/08887 CLASSIFICATION OF SUBJECT MATTER IPC 5 A61K47/10 A61K9/O According to Internatonal Patent Olssification (IPC) of to both national classufication and IPC B. FIELDS SEARCHED Minimum documntuon searched (classification system followed by clssification symbols) IPC 5 A61K Documentation searched other tha minimum documentation to the extent that such documents arm included in the fields searched Electronic data base consulted. during the snternatoal search (name of data base and, where practical, search termsl used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of documnent, with indication where appropriate, of the relevant panag Relevant to claim No. PX WO,A,92 17164 (THE PROCTER GAMBLE 1-8 COMPANY) 15 October 1992 Y see claims 1,3,5,10,11 1-8 see page 5, line 16 -line 24 see page 6, line 1 -line 11 Y I FR,A,2 127 011 (WILKINSON SWORD LIMITED) 1-8 13 October 1972 see claim 1 see page 10, line 5 line 22 D Further documertis arc listed in the continuation of box C. L Patent familyI mbax am listed in anniCL *Special categories of cited documens: later document publihed after the interntational filing date or priority date and not in conflict with the appliaton but document defining the general stal of the art which is not cited to understand the principle or theory uniderlying the condered to be of particular relevanceineto earlier document but pubished on or after the international 'XI document of particular relevance; the claimed invention filinigdte cannot be condered novel or cannot he considered to WL documenit which may throw doubts on priority daim(s) or involve an inventive step when the document is taken filone which is cited to establis the publication date of another document of particular relevance; the claimed invention citation or other speesal reawn (as specified) cannot be considered to involve an inventive step whtm the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such coniliation being obvious to a person skilled document published prior to the international filing datebut in the art. later than the priority date climed W& document immber of the same patent family Daue of the actual coipletion of the international search Date of mailing of the intemnational search report 29 April 1994 1 8.01594~ Name and mailing addrias of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV isijk Td. (-i31-70) 340-2D40, T31651 epo nl, Ventura Amat, A Faxc (,31-70) 340-3016 Form PCT/1SA/10 (ae si set) (July 1992) INTERNATIONAL SEARCH REPORT. Intern, nAl Applicavon No wf r ai on patent (a l~y m a b cr P C 1 i U S 9 3 /0 8 8 8 7 Patent document I Publication IPatent family I Publication cited in search report date member(s) I date W-A-9217164 15-10-92 AU-A- 1761492 02-11-92 EP-A- 0578768 19-01-94 US-A- 5244670 14-09-93 FR-A-2127011 13-10-72 AT-B- 335069 25-02-77 AU-B- 457073 23-12-74 AU-A- 3860572 09-08-73 AU-B- 450078 07-06-74 AU-A- 3860672 09-08-73 BE-A- 778950 04-08-72 BE-A- 778951 04-08-72 CA-A- 968141 27-05-75 CA-A- 1019551 25-10-77 CH-A- 549952 14-06-74 CH-A- 554648 15-10-74 DE-A,B,C 2202535 17-08-72 DE-A- 2203947 17-08-72 FR-A,B 2127010 13-10-72 GB-A- 1353381 15-05-74 LU-A- 64713 30-06-72 NL-A- 7201522 08-08-72 NL-A- 7201524 08-08-72 SE-B- 402404 03-07-78 US-A- 4193936 18-03-80 US-A- 4178459 11-12-79 US-A- 4226988 07-10-80 US-A- 4136163 23-01-79 US-A- 4150052 17-04-79 US-A- 4190643 26-02-80 In Form PCT/ISN/210 (patnt hauniy annex) (July 1992)