Patented Oct. 11, 1949 2,484,637

UNITED’ STATES PATENT OFFICE 2,484,637 POWDERED OINTMENT BASE OF METHYL CELLULOSE AND SORBITOL Albert M. Mattocks, Jr., and Wilbur A. Lazler, Birmingham, Ala., assignors to Southern Re search Institute, Birmingham, Ala., a corpora tion of Alabama No Drawing. Application August 20, 1946, ‘ Serial No. 691,867 . ' 1 Claim. (Cl. 167—63) 1 This invention relates to new therapeutic prep were encountered in the general use of such an arations and more particularly refers to dry, ointment since the prepared paste was biologically stable therapeutic powders capable on addition unstable and it was troublesome to prepare it in of Water of rapid transformation into gelatinous fresh condition as needed. ointments or ointment vehicles. From the foregoing it is evident that despite It is well known in the pharmaceutical ?eld the great need for hydrophilic ointments, the that the formulation, storage, and dispensing of difficulty of storing them“ or preparing them when drugs in water-miscible solid vehicles has pre needed has been such that these ointments have sented such extraordinary dif?culties that hydro not received the widespread use which their effec philic ointments have been very little used. Wet 10 tiveness warrants. This is true not only for oint . jellies such as starch paste and colloidal suspen ments which are particularly adapted for the sions of the soluble proteins and vegetable gums treatment of burns but also for hydrophilic oint not only are bulky and tend to “leak” as a result ments generally as vehicles for the application of of syneresis, but often give rise to various forms medicaments to the skin. of microbial deterioration. Moreover, they tend 15 It is an object of this invention to produce an to dry out, thus defeating the purpose for which entirely new class of easily wettable therapeutic they were compounded. Once dried, it is well ointment powders. It is a further object to pro known that such ointment bases are not easily duce ointments in powder form that are compact, rehydrated to give jellies having the proper tex biologically and chemically stable, and easily and 20 ture. ' quickly convertible on addition of water into ther Notwithstanding the foregoing difficulties, oint apeutically active jellies suitable for the treatment ment bases of hydrophilic character have been of wounds. A still further object is to produce demonstrated repeatedly to be useful in releasing an ointment vehicle in powder form having the medicaments for absorption through the skin, aforesaid properties, to which may be added what when applied to local areas of the body. For 25 ever medicament is desired at the time of use. example, extensive experiments in the use of sulfa Additional objects will become apparent from a , drugs have indicated the superiority of water consideration of the following description and dispersible preparations for the application of claims. these compounds. In the same manner, clinical These objects are attained in accordance with tests have demonstrated the value of hydrophilic 30 the present invention by mixing a cellulose ether ointments as a means of bringing powerful anti with a wetting agent and ?nely comminuting biotics into contact with surfaces of the body. the mixture either before or after incorporation A special problem in this connection is removal therein of the desired medicament. In a more of necrotic tissue from the site of burned tissue. restricted sense this invention is concerned with~ The removal of such tissue is important to avoid dry, stable therapeutic powders which speedily infection and permit granulation ofv new tissue dissolve in water to form jellies capable of pro which protects and heals the wound. In the past, ducing an adherent coating over wounds com mechanical debridement of burns by scrubbing prising a finely comminuted cellulose ether or surgery was common, but it caused consider throughout which is uniformly incorporated a able, pain and increased the danger from shock. 40 wetting agent, and if desired, a medicament. In In addition, it has been found to damage or re its preferred embodiment the cellulose ether is move residual islands of epithelial cells capable methyl cellulose and the wetting agent is sorbitol. of regenerating new tissue. Ethers of cellulose have been found to be sur~ In an endeavor to avoid the disadvantages of prisingly satisfactory swelling agents for the the customary mechanical debridement treatment powders of this invention since they are substan for burns, attempts have been made to remove tially unattacked by microorganisms, remain necrotis tissue therefrom by chemical means. stable when stored under widely varying condi G. Connor and S. C. Harvey (Ann. Surgery 120, tions, and form excellent jellies when dissolved 362 (1944)) found that jells containing organic in water. Unfortunately, cellulose ethers are acids such as pyruvic acid or succinic acids cause notoriously slow in dissolving in water, as a result removal of slough in a single tough pellicle, leav of which their application for therapeutic pur ing a clean granulating surface. Connor and poses has been seriously retarded. For instance, Harvey used cornstarch paste containing pyruvic when a chemist wishes to make an aqueous solu acid in a sufficient concentration to yield a jelly tion of methyl cellulose he ordinarily soaks it in having a pH of 1.9. Serious objections, however, cold water in a refrigerator overnight. If one adds 2,484,687 3 4 sorbitol or some other wetting agent to the water agent may be carried out in avariety of standard the time required to dissolve the cellulose ether mills such as the micropulverizer, the ball mill, is not substantially lowered. the hammer mill, the burr mill, or the micronizer. _ We have found that by mixing sorbitol or This invention may be more readily understood other suitable wetting agent with the cellulose by a consideration of the following illustrative ether and ?nely comminuting the mixture in a examples wherein the vquantities, unless other hammer mill or other efficient grinding device, a wise indicated, are stated in parts by weight. dry, stable powder is obtained which dissolves in water almost instantaneously, in contrast with Example 1 the inordinate periods formerly considered to be One hundred parts of methyl cellulose and 20 essential. In accordance with this invention, the parts of an 85% aqueous solution of sorbitol was powdered cellulose ether may be mixed in a dry thoroughly mixed and passed several times form with a wetting agent to which has been through a hammer mill. The product was a ?ne added, if desired, a medicament, and the mixture white powder. Whereas the original methyl cel thereafter ?nely comminuted by passing through lulose dissolved very slowly, it was found that the a hammer mill or similar device. However, op ?ne powder produced as aforesaid could be easily timum results are obtained if the cellulose ether wetted in less than a minute. is ?rst added to an aqueous solution of the wet ting agent (with or without medicament) and Example 2 the mixture stirred for a prolonged period until One hundred parts of methyl cellulose was in a homogeneous ointment is formed. Thereafter corporated with 20 parts of Xynomine (wetting this ointment is dehydrated in thin layers, such agent) and 9.5 parts of pyruvic acid. The mix as by spreading the mixture on sheets of glass ture was ?nely ground in a hammer mill until in layers about one-half centimeter thick and the whole mass would easily pass through a ?ne drying for 24 hours in an oven’ at about 75° C. - screen. The resulting ?ne white powder had a The dehydrated sheets thus produced are then fluffy appearance and swelled rapidly in eight ?nely comminuted in a pulverizing mill. The re ‘parts of water to give a. sticky semitransparent sulting powder has the surprising property of paste of a proper consistency for application as completely redissolving in water in approximately an ointment. The acidityof the aqueous oint 1 minute, so that it can be converted to an oint ment measured pH 1.87. The ointment was found ment whenever needed, and if desired medica to be very effective when applied as a dressing for ment may be added at the time of use. the debridementiof thermal or chemical burns. By the unique methods referred to above we Example 3 have succeeded for the ?rst time in preparing dry, easily wettable, biologically stable, solid ther- ' One hundred parts of methyl cellulose, 20 parts apeutic ointment bases wherein the gelling agent of 85% sorbitol syrup, and 12.3 parts of pyruvic is a cellulose ether. These powders may have acid was thoroughly mixed and passed through a the medicament incorporated therewith before pulverizing mill. The resulting ?ne powder wet comminution in the manner referred to previous ted with water in 2 minutes to give a clear jelly, ly. or if=an all-purpose ointment vehicle is de having a pH of 2.28. Similarly, another acid de sired the medicament may be omitted, to be bridement composition was prepared by substi added at the time of use. Preparation of these tuting 16.7 parts of phosphoric acid for the pvru powders with methyl cellulose, hydroxyethyl‘ cel vic acid used above. The pH of this composition lulose or other cellulose ethers as the gelling was 1.6. agents, imparts speci?c desirable characteristics 45 to the resulting ointments. These agents have Example 4 good body and cling to undersurfaces without One hundred parts of high viscosity hydroxy tendency to ?ow. They are free from irritation ethyl cellulose was formulated with 8.9 parts of and are inert towards microbial attack. Their pyruvic acid and 25 parts of Arlacel C (wetting viscosities may be varied within a wide range by 50 agent). After thorough grinding in a pulveriz varying’ the amount of wetting agent and the ing mill the mixture dissolved to a clear jelly amount of water added thereto. in a matter of a few minutes as compared with While methyl cellulose is a preferred cellulose several hours for the untreated hydroxylethyl ether, it has been found that ethyl cellulose, cellulose. ’ propyl cellulose, and related ethers may be em 55 Example 5 ployed. Likewise. substituted cellulose ethers such as hydroxyethyl cellulose and cellulose gly One hundred and ?fty parts of methyl cellu collic acid may be used. These cellulose ethers lose, thirty parts of sorbitol, and two thousand may be employed alone or in admixture with one parts of water were mixed with a mechanical another, and it is contemplated that other gelling 60 stirrer until a homogenous mixture was ob agents may be added thereto although for opti tained. One hundred and nine parts of colloidal mum results it is preferred to employ only cellu sulfur was thoroughly incorporated in the gel, and lose ethers for this purpose. the smooth paste was dried on glass plates in sorbitol is the preferred wetting agent. How thin layers at 75° C. for twenty-four hours. The ever. other wetting agents may be employed and 65 dry ?lm was ground to a ?ne powder to form a in particular those wetting agents commonly medicated base that could be quickly wetted with known as non-polar or non-ionic wetting agents. the calculated amount of water to form a ?ve The non-ionic wetting agents mav be illustrated per cent sulfur ointment. by the well known polyhydric alcohols and their Example 6 ethers and esters. Since sorbitol is a solid, non 70 toxic material it is ideally suited for employment Fifty parts of methyl cellulose. ten parts of as a wetting agent in the compounds of this sorbitol, and six hundred and sixty-seven parts of invention. water were mixed with a mechanical stirring de The grinding operation which is essential to vice until a homogenous gel was‘ formed. Three and six-tenths parts of local anesthetic. pro ?nely comminute the cellulose ether and wetting caine-hydrochloride, was added and mixed thor 2,484,887 5 6 oughly with the gel. After drying in thin layers formed. A solution of one hundred and nine at 75° C. for twenty-four hours, the mass was parts of mercurochrome in ?ve hundred parts of ?nely pulverized. The resultant dry powder water was added and mixed thoroughly with the speedily wetted with water to form an ointment gel. The mass was dried in a'stream of warm wtih local anesthetic properties. air for twenty-four hours'and then ?nely pul verized. The resultant dry powder speedily wet Example 7 ted with water to form an ointment with anti One hundred and ?fty parts of methyl cellu septic properties. lose, thirty parts of sorbitol, and two thousand Example 13 parts of water were mixed with a mechanical stir 10 One'hundred and ?fty parts of methyl cellu ring device until a homogenous gel was formed. lose, thirty parts of sorbitol, and two thousand Ten and nine-tenths parts of ephedrine hydro parts of distilled water were mixed with a me chloride dissolved in three hundred parts of wa chanical stirring device until a homogenous gel ter was added and mixed thoroughly with the gel. was formed. A solution of ten and nine-tenths The mass was dried in thin layers at 75° C. for 15 parts of silver nitrate dissolved in one thousand twenty-four hours and then ?nely pulverized. parts of water was added and mixed thoroughly On wetting with water, the powder dissolved rap— with the gel. The mass was dried in thin layers idly to form a clear ointment with vasoconstric at 75° C. for twenty-four hours and then ?nely tor properties. pulverized. The resultant dry powder speedily Example 8 20 wetted with water to form an ointment with an One hundred and ?fty parts of methyl cellu tiseptic properties. lose, thirty parts of sorbitol, and two thousand Example 14 parts of water were mixed in a power driven mix er until a homogenous gel was formed. Two To one hundred parts of ?nely powdered hy hundred and eighteen parts of ?nely powdered droxyethyl cellulose (high viscosity) was added salicylic acid and one hundred and nine parts with thorough mixing a solution of twenty-?ve of ?nely powdered benzoic acid were added and parts of Arlacel C (wetting agent) and four and mixed thoroughly with the gel. The mass was eighty-?ve hundredths parts of pyruvic acid in dried in a stream of warm air 100° C. until a dry ?ve hundred parts of acetone. The acetone was ?lm was obtained and then ?nely pulverized. then evaporated from the mixture, and the re The resultant dry powder was easily wettable sidual mass was ground to a ?ne powder in a with water to form an ointment useful for treat hammer mill. One part of this powder wetted ment of skin diseases. readily with three parts of water to yield an ointment of pH 2.50 suitable for use in the de Example 9 - bridement of burns. One hundred parts of methyl cellulose, twenty ’ Example 15 parts of sorbitol, one thousand three hundred and thirty-three parts of water were mixed with One hundred and ?fty parts of methyl cellulose, a mechanical stirring device until a homogenous thirty parts of sorbitol, and two thousand parts gel was formed. Seventy-two parts of ?nely pow of water were mixed with a mechanical stirring dered yellow mercuric oxide were added and mixed device until a homogenous gel was formed. One thoroughly with the gel. The mass was dried hundred and nine parts of sulfathiazole, ?nely in thin layers at 75° C. for twenty-four hours powdered, was added and mixed thoroughly with and then ?nely pulverized. the gel. The mass was dried in thin layers at . 75° C. for twenty-four hours and then ?nely pul Example 10 verized. The resultant dry powder readily wetted One hundred and ?fty parts of methyl cellu with water to form an ointment useful for treat lose, thirty parts of sorbitol, and two thousand ment of infections. A similar ointment was pre parts of water were mixed with a mechanical pared in a like manner from methyl cellulose, stirring device until a homogenous gel was 50 sorbitol, and sulfadiazine. formed. Twenty-one and eight-tenths parts of Example 16 lactic acid was added and mixed thoroughly with the gel. The mass was dried in thin layers at One hundred and ?fty parts of methyl cellulose,v 75°~ C. for twenty-four hours and then ?nely pul thirty parts of sorbitol, and two thousand parts verized. The resultant dry powder speedily wet of water were mixed with a mechanical stirring ted with water to form an ointment with contra device until a homogenous gel was formed. One ceptive properties. hundred and nine parts of sulfanilamide, ?nely Example 11 powdered, was added and mixed thoroughly with the gel. The mass was dried in thin layers at 75° One hundred and ?fty parts of methyl cellu 60 C. for twenty-four hours and then ?nely pulver lose, thirty parts of sorbitol, and two thousand ized. The resultant dry powder readily wetted parts of water were thoroughly mixed over a pe with water to form an ointment useful for treat riod of time su?icient to swell and uniformly in ment of infections. ' corporated them into a homogenous gel. One hundred and nine parts of argyrol dissolved in Example 17 ?ve hundred parts of water were added and mixed One hundred and ?fty parts of methyl cellulose, thoroughly with the gel. The mass was dried thirty parts of sorbitol, and two thousand parts and then ?nely pulverized. The resultant dry of warm water containing one hundred and nine powder readily wetted with water to form an parts boric acid were mixed until a. homogenous ointment with antiseptic properties. 70 gel was formed. The mass was dried in layers Example 12 and pulverized. The powder readily formed on One hundred and ?fty parts of methyl cellu addition of water an antiseptic ointment. lose, thirty parts of sorbitol, and two thousand It is to be understood that the individual com parts’ of water were mixed with a mechanical ponents and the amounts thereof referred to in stirring device until a homogenous gel was 75 the preceding examples may be varied widely 2,484,887 8 without departing from the scopeof this inven therapeutic purposes. These ointments and oint tion. As mentioned previously, other cellulose ment bases are free from the many disadvantages ethers, as well as other wetting agents, may be which have heretofore precluded the use of water employed in the above examples in lieu of methyl miscible, solid vehicles in the pharmaceutical in-, cellulose and sorbitol. Likewise, mixtures of cel dustry. They are dry, stable powders which may lulose ethers or wetting agents may be used. The be stored for long periods, but which dissolve read amount of cellulose ether is of course substan tially larger than the amount of wetting agent. ily in water when needed to produce an ointment As a general rule, for 100 parts by weight of cel 0r ointment vehicle of the desired characteristics. lulose ether approximately 10 to 40 parts by As many apparently widely different embodi weight of wetting agent is suf?cient. ments of this invention may be made without de parting from the spirit and scope hereof, it is to When the medicament is to be added to‘ the be understood that the invention is not limited ointment bale at the time of preparation thereof to the speci?c. embodiments hereof except as any desired concentration necessary for the par de?ned in the appended claim. ticular purpose to which the ointment is to be 15 We claim: v applied may be used. As a general rule, the A biologically and chemically stable ointment medicament will vary from less than 1% to as base in the form of a dry powder comprising a high as 10 or 15% by weight of the ointment base, ?nely comminuted mixture of methyl cellulose although larger amounts may be used if desired. and sorbitol containing from 10 to 40 parts by A wide variety of medicaments or mixtures ~ weight of sorbitol for each 100 parts by weight thereof may be employed. Where the medic of methyl cellulose, said powder being readily ament is to be added to the ointment base when soluble in water in approximately one minute. the latter is prepared it is of course advisable ALBERT M. MATTOCKS, JR. that it be stable on storage. If a medicament is WILBUR A. LAZIER. unstable under the conditions of storage then it should be added to the ointment vehicle at the REFERENCES CITED time the latter is dissolved in water, just prior to application to the wound. The following references are of record in the file of this patent: A representative group of medicaments which may be incorporated in the ointment bases of the 30 UNITED STATES PATENTS present invention includes mercurochrome, sulfa pyridine, sulfathiazole, sulfadiazine, bichloride of Number Name , Date mercury, silver nitrate, argyrol, boric acid, phos 2,288,200 Meyer ______June 30, 1942 phoric acid, pyruvic acid; anesthetic agents such 2,321,270 Bacon et a1. ______June 8. 1943 as procaine and butycaine; vasoconstrictors such 35 FOREIGN PATENTS as epinephrine and cocaine; antiseptics such as Number Country Date salicylic and benzoic acids and derivatives, zinc 156,725 Great Britain ______July 7, 1922 and mercury oxides, calamine, phenol, and cresol; 514,354 Great Britain ______Jan. 25, 1938 oxidizing agents such as the more stable peroxides 739,630 Germany ______Sept. 30, 1943 and chloramines; counter irritants such as mus tard oil, menthol, eucalyptol, and camphor; coal OTHER REFERENCES tar products commonly used as parasiticides and Speel, American J. Pharm., April, 1941. (Copy for dermatitis; spermacides and contraceptive in Division 43.) agents such as thymol and its derivatives, hexyl Drugand Cosmetic Industry, September 1944, resorcinol and hydroxyquinolines; colloidal silver 45 page 345. (Copy in Division 43.) '_ proteins and protamines for treatment of infec Pickrell, J. A. P. A. Prac. Pharm. ed., Nov. 1942. tious diseases; hormones such as testosterone and (Copy in Division 43.) estrin for topical application, etc. Market, J. A. P. A. Abstract Section 1943, page By means of the present invention an im 13. (Copy in Division 43.) portant class of new hydrophilic ointments and 50 Connor et al., Squibb Abstract Bulletin, Dec. 27, ointment bases has been made available for 1944, vol. 17, page 2198. (Copy in Division 43.)