Topical treatment of acne with cephalosporins

41 Pages·2013·4.26 MB·English

_ USOO5409917A
Unlted States Patent [191 [11] Patent Number: 5,409,917
Robinson et a1. [45] Date of Patent: Apr. 25, 1995
[54] TOPICAL TREATMENT OF ACNE .WITH [56] References Cited
CEPHALOSPORINS U.S. PATENT DOCUMENTS
[75] Inventors: Howard N. Robinson, Lutherville; 4’444’755 4'/ 1984 Horrob' m ........................ 42 4 / 145
Neil F. Martin, Potomac, both of FOREIGN PATENT DOCUMENTS
Md' 0005348 11/1979 European Pat. Off. .
[73] Assignees: Marvin S. Towsend, Towson; OTHER PUBLICATIONS
Leonard Bloom, Rockville, both of Fisher, Current Contact News, 25, 1980, p. 474.
Md.; a part interest to each Frank, Postgrad. Med., 61, (6), 1977.
Primary Examiner-Gollamudi S. Kishore
[21] Appl. No.: 126,799 Attorney, Agent, or Firm—Leonard Bloom; Marvin S.
Towsend
[22] Filed: Sep. 24, 1993, [57] ABSTRACT
A method and composition for topically treating acne
Related Us. Application Data and acneiform dermal disordersincludes applylng an
_ _ _ amount of a cephalosporm antlblotlc effectlve to treat
[63] comlmlatlomn-pm Of Ser- _N0; 383,914; M45’ 12, the acne and acneiform dermal disorders. The antibiotic
1992’ Pat' N°' 53601292’ whlch ‘5 a mmmuatlcm'm' is blended with a carrier suitable for topical application
Part of Se" No‘ 664’795' Mar‘ 5’ 1991' abandoned- to dermal tissues. The carrier is selected from the group
consisting of an aqueous liquid, an alcohol base, a water
[51] Int. C1.6 ....................................... A61K 31/545 soluble gel, a lotion, an ointment, a nonaqueous liquid
[52] US. Cl. .................................. .. 514/200; 514/201; base, a mineral Oil base, a blend of mineral oil and petro
514/202; 514/203; 5l4/204; 514/205; 514/206; latum, liposomes, a time-release patch, and a liquid
514/207; 514/208; 514/209; 514/159; 514/557; absorbed wipe. The cephalosporin can also be com
_ 514/714; 514/725; 424/703; 424/401 bined with benzoyl peroxide in a gel carrier.
[58] Field of Search .............................. .. 5l4/200-210,
514/886, 887, 159, 714, 557, 725; 424/703, 401 14 Claims, No Drawings
5,409,917
1 2
ing. In moderately active cases, larger cystic lesions can
TOPICAL TREATMENT OF ACNE WITH develop.
CEPHALOSPORINS Acne vulgaris can appear in many clinical varieties.
The mildest case manifests comedones on oily skin and
CROSS-REFERENCE TO RELATED S is called acne comedo.
APPLICATION Papular acne is another variety of acne which has
many in?ammatory papules. This form of acne is com
The present application is a continuation-in-part ap
mon in adolescent skin, but it can be seen in all ages.
plication of Ser. No. 07/883,914, ?led May 12, 1992,
The papular in?ammatory form of acne can progress to
entitled TOPICAL TREATMENT OF ACNE WITH
an indurated, deeper, and destructive form known as
AMINOPENICILLINS, now US. Pat. No. 5,260,292.
acne indurata. These lesions can produce severe scar
Patent application Ser. No. 07/883,914, ?led May 12,
ring and can be quite deep seated and destructive.
1992 is a ?le wrapper continuation-impart application of
Steroid acne vulgaris can occur when oral cortico
parent application Ser. No. 07/664,795, ?led Mar. 5,
steroids or topical steroids are used and occurs as in
1991, by the same inventors, entitled TOPICAL
15 ?ammatory follicular papules. When oral corticoster
TREATMENT OF ACNE, now abandoned.
oids are ingested, the in?ammatory papules are usually
FIELD OF THE INVENTION sudden in appearance and can cover the chest, back,
arm, and face. When topical corticosteroids are used for
The present invention relates to the ?eld of treating
more than two weeks, a localized in?ammatory papular
the skin condition known as acne. More speci?cally, the
response can develop which can proceed to a granu
present invention is concerned with the prophylactic or
lomatous chronic reaction known as steroid acne rosa
therapeutic topical treatment acne. Even more speci?
cally, the present invention is concerned with the topi cea.
Premenstrual acne can occur in a large number of
cal treatment of acneiforrn dermal conditions such as
menstruating women as a papular and pustular acne
acne vulgaris, preadolescent acne, acne rosacea (now
25 vulgaris, approximately one week prior to menstrua
known as rosacea), premenstrual acne, acne venenata,
tion. There is a body of evidence that implicates a surge
acne cosmetica, pomade acne, acne detergicans, acne
in progesterone as the mediator of premenstrual acne.
cosmetica, acne excoriee, gram negative acne, steroid
Preadolescent acne is divided into neonatal, infantile,
acne, acne conglobata, or nodulocystic acne. The pres
and childhood forms of acne. The neonatal form is
ent invention can also be used for topically treating
limited to the ?rst few weeks of life. It usually develops
certain types of dermatitis, e. g. perioral dermatitis,
a couple of days after birth. It more commonly af?icts
seborrheic dermatitis, gram negative folliculitis, seba
males and reveals transient facial papules and pustules
ceous gland dysfunction, hidradenitis suppurativa,
which can clear spontaneously in a few days or weeks.
pseudofolliculitis barbae, or folliculitis.
The stimulation of neonatal sebaceous glands by circu
BACKGROUND OF THE INVENTION 35 lating maternal progesterone appears to be the cause.
If the acne persists beyond the ?rst month of life, the
Acne vulgaris is a common disease which afflicts
acne is called infantile acne and can extend into child
approximately 90% of all teenagers, and, not uncom
hood, adolescence, and adult life. The childhood acne
monly, affects men and women in their twenties or
can result from a persistent infantile acne or can develop
thirties or may persist in adults for many years. Acne
40 de novo after age two. This form of acne is uncommon,
vulgan's most commonly occurs on oily areas of the skin but it has more of a male predilection. It is characterized
with high sebaceous gland concentration. The areas of by comedones commonly in groups, papules, pustules,
high sebaceous gland concentration are the face, ears, and, rarely, cysts. This condition can extend from a few
retroauricular areas (e. g. behind the ears), chest, back, weeks to several years and can develop into pubertal
and occasionally the neck and upper arms. , 45 acne.
Acneiform eruptions can occur wherever there is a Acne venenata is by de?nition a comedonal or papu
pilosebaceous unit or sebaceous follicle which does lar acne which occurs after exposure to chlorinated
include the entire surface of the skin. hydrocarbons (chloracne), cutting oils, petroleum oil,
The basic lesion in acne is the comedo commonly coal tar, and pitches.
known as the blackhead. The comedo is created by Acne cosmetica is a persistent low grade comedonal
retention of layers of dead skin known as keratin in the and/ or papular and pustular acne that occurs usually on
lining of the follicles. In addition to hyperkeratosis the chin and cheeks of adult women due to oil-based
(which is thickening or retentative layering of keratin), cosmetics, i. e. foundations, facial creams, and sun
there is an accumulation of sebum which is the lipid
screens.
laden product of the sebaceous gland. The cells of the Pomade acne is a type of acne cosmetica which ap
sebaceous glands in which sebum originates are the pears to occur almost exclusively in black persons who
sebocytes. The combination of the keratin and the apply grease and oil to scalp hair and the face as a
sebum produces a plugging of the mouth or opening of grooming aid. The lesions are predominately come
the follicular canal, and papules are formed by in?am donal acne and can develop into in?ammatory acne
mation around the comedones (plural of comedo). De 60 papules, depending upon the chronicity of the pomade
pending upon the degree of inflammation, pustules,
use.
cysts, nodules, granulomatous reactions, scars, and ke Acne detergicans occurs as a type of comedonal acne
loids may develop. in patients who use oil-based cleansing soaps. Acne
Most typical forms of mild acne vulgaris demonstrate excoriee, also known as pickers acne, starts out as mild
the predominance of comedones with the occasional 65 form of papular or comedonal acne which is manipu
pustules. Pustules and papules predominate in more lated or picked and causes further in?ammation, more
severe cases. These can heal with scars forming; that is, papules, and sometimes scars, pitting, and atrophy of
?brosis of the lesions occurs that are deep and penetrat the skin.
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Gram negative acne, sometimes called gram negative There is a genetic tendency to acne, in particular acne
folliculitis when it extends to the neck, arms, legs, and congoblata which is a deep cystic and sinus forming
trunk, is a form of an in?ammatory papular, follicular, type of acne. This condition is essentially a deep, ag
and pustular response to gram negative organisms in gressive form of cystic acne occurring in the apocrine
cluding Enterobacter, Klebsiella, Escherichia, Proteus, gland regions. Topical administration of clindamycin
Serratia, and Pseudomonas. The most characteristic has been used to treat this form of cystic acne.
lesion on the face is super?cial pustules, or papulo-pus The etiology of acne vulgaris and related disorders as
tules (which is a combination of a papule and pustule). discussed above is not completely known in every de
The face can show diffuse erythema and in?ammation tail. However, what is known is that acne, in general, is
surrounding these pustules and juicy papules or papulo caused by a plurality of factors. In general, there are
pustules.
four main factors that cause acne: genetics; hormonal
The gram negative acne is usually highly resistant activity; bacteria; and the in?ammatory response.
and usually occurs in patients who have bad in?amma Genetics is a prominent component as it is well
tory papular acne for long periods or who have been known that several members of the same family can be
treated with long term oral administration of antibiotics p.. 5 affected with moderate to severe scarring acne. The
such as tetracycline, erythromycin, or minocycline or inheritance by some is thought to be autosomal domi
topical antibiotics such as topical clindamycin or topical nant, but this has not been de?nitively proven. Further
erythromycin. Subsequent to the oral administration more, on the molecular level, there has not yet been
tetracycline or erythromycin, oral administration of discovered a gene or group of genes that are responsible
amoxicillin, ampicillin, and trimethoprin-sulfomethox for the various forms of acne vulgaris.
azole has been shown to be effective in treating this Another key factor in the development of acne is
disease. (Poli, F., Prost, C., Revuz, J ., Gram-negative hormonal. In adolescence, for example, it is thought
Folliculitis, Ann. Dermatol. Venereol., 115:797-800, that androgens can interact with receptors on the seba
1988). In another reference, Marks, R. and Ellis, J., ceous glands and cause stimulation of the sebaceous
“Comparative effectiveness of tetracycline and ampicil gland to hypertrophy vand hence form more sebaceous
lin in rosacea”, Lancet 1971 vol 2 pages l049—1052, production of lipids and free fatty acids which distend
there is a disclosure that ampicillin has been used orally the follicular canal. More speci?cally, there is evidence
for treatment of rosacea. More speci?cally, orally ad for increased peripheral metabolic conversion of the
ministered ampicillin was compared with orally admin androgen testosterone to dihydrotestosterone at the
istered tetracycline in the treatment of rosacea. level of the skin in acne patients. It is further hypothe
Acne rosacea is an in?ammatory eruption that is sized that receptors on the sebaceous gland for the ac
chronic and occurs on the face, especially on the nose as tive androgen dihydrotestosterone can exhibit various
well as the scalp and neck, in some instances. It is mani degrees of sensitivity, and that a heightened sensitivity
fested by erythema, pustules, papules, telangieclasia response may be partially or entirely genetically prede
(which is dilation of super?cial capillaries), and hyper termined.
trophy of sebaceous glands. The middle portions of the Another causative factor in acne is the presence of
face are most frequently involved. The eyes and eyelids bacteria in the follicular canal. Within the follicular
are not uncommonly involved and can produce in?am canal are bacteria which are indigenous to the follicular
mation and infection of the conjunctiva, eyelids, and lining. They are anaerobic, gram positive organisms
hypertrophy of the meibomian glands. Acne rosacea is called Propionibacterium acnes. It is interesting to note
often called simply rosacea and is most common in that they are present in abundance in pathologically
middle aged women and men. Rosacea can go on to affected sites. They are reduced during oral antimicro
form a granulamatous roscea which is characterized by bial treatment, and their absence from nonhuman animal
resistant in?ammatory papules which when biopsied skin is striking especially since animals do not exhibit
reveal noncaseating epithelial cell granulomas. 45 acne vulgaris.
Pseudofolliculitis barbae is a predominantly male Yet another causative factor in acne is the in?amma
affliction which is characterized by in?ammatory tory response manifested in the skin. More speci?cally,
papules and pustules on the bearded area of the face it is thought that Propionibacterium acnes lives in sym
most commonly in black persons, but all racial groups biosis on the keratin lined follicular canal. Propionibac
can be affected. The mechanism is thought to be an terium acnes ingests the sebum produced from the sebo
in?ammatory response to the end of hair (usually curly cytes of the sebaceous glands. This nascent sebum is
beard facial hair) into the skin causing a foreign body largely lipid in composition and also contains DNA,
in?ammatory response. RNA, proteins, and other cellular components that
Folliculitis is an in?ammatory reaction around the result from the breakdown of sebocytes themselves.
hair follicle which can be bacterial or nonbacterial in 55 The Propionibacterium acnes which are highly lipo
nature. Predominately, folliculitis is caused by gram philic, feed on the nascent sebum. It has been shown
positive organisms such as Staphylococcus and Strepto that Propionibacterium acnes are found only in seba
coccus, and less frequently by gram negative bacteria ceous rich areas. If the nutrients increase due to an
discussed hereinabove with respect to gram negative active and large sebaceous system, then colonization
folliculitis. and high growth rates of Propionibacterium acnes will
Perioral dermatitis is a common papular in?amma form. It has been shown that the resident bacterial ?ora
tory eruption which is con?ned around the mouth. It will produce biologically active molecules such as hista
most commonly af?icts women in their early twenties mine, extracellular enzymes, and peptides which may be
to middle thirties, but it can be seen in adolescents and responsible for the chemotaxis of the in?ammatory
more mature adults. 65 in?ltrate in acne vulgaris. Since the follicular lining in
Hidradenitis suppurativa is a suppurative (chronic) the pilosebaceous unit is intact, it has been theorized
and cystic disease of apocrine gland regions of the skin, that if colonization of Propionibacterium acnes occurs
including the axillae and groin. in suf?cient numbers, they could produce initiating
5,409,917
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autogenic molecules that promote the initiating of in cosamine and glucuronic acid units) bonded to a bridg
?ammation. Propionibacterium acnes can produce ing agent (which is cyanogen bromide) which, in turn,
proteinases, lipase, and hyaluronate lyase all of which is bonded to the amino-nitrogen atom of the aminopeni
may serve as the catalysts or initiators of the in?amma cillin, ampicillin. Thus, with this hyaluronic acid deriv
tory in?ltrate which has been shown to be composed of 5 ative, the amino-nitrogen of the aminopenicillin is no
neutrophils and lymphocytes. longer in the form of a primary amino group. This hya
A number of treatments are presently known for luronic acid derivative is disclosed in Great Britain
treating acne, some more successful than others. Some Published Application 2,207,142.
modes of treatment have been mentioned above. There Still other topical treatments for acne using anti-bac
are two basic ways to administer a therapeutic agent: terials are described in the following U.S. patents: an
topical and systemic. azole derivative in conjunction with benzoyl peroxide,
Aside from treatments mentioned above, some addi U.S. Pat. No. 4,446,145, incorporated herein by refer
tional systemic treatments for acne that are presently ence; and metronidazole in a special gel as described in
employed are: oral tetracycline; oral erythromycin; U.S. Pat. No. 4,837,378, incorporated herein by refer
minocycline; doxycycline; oral trimethoprim-sulfame pl 5 ence.
thoxazole and isotretinoin (ACCUTANE TM). It is noted that none of the topical treatments men
Those that have been suggested in the past and that tioned above disclose the treatment of acne topically
are no longer generally employed include: antibacterial with a cephalosporin.
vaccines; estrogen therapy; dietary restrictions; and It is recalled that the applicants parent US. patent
vitamin therapy (e. g. oral ingestion of vitamin A). application was ?led Mar. 5, 1991. In addition, prior art
Some of the topical treatments that are presently treatments and proposed treatments for acne have
employed are: topical erythromycin, clindamycin, ben spanned many years and have been published in a large
zoyl peroxide, 2% sulfur, 3% resorcinol, a tetracycline number of publications, some of which are discussed
derivative (meclocycline sulfosalicylate 1%), 2% sali above and some of which are discussed below.
cylic acid, and tretinoin (Retin-A TM). 25 In Kirk-Othmer, Encyclopedia of Chemical Technol
Topical treatments that have been suggested in the ogy, Third Edition, Volume 2, (1978), page 812, there is
past and that are no longer generally employed include: Table 2 in which it is disclosed that cephalosporin C, N,
x-ray treatment; electric sparks; vitamin therapy; treat P were discovered in 1948; cephalothin was discovered
ment with a plant extract as described in U.S. Pat. No. in 1962; and cephalexin was discovered in 1967.
4,803,069. 30 In Frank, “Treatment of Acne with Topical Antibiot
More speci?cally with respect to the topical use of ics”, Postgrad. Med., 61(6):92-8, June 1977, there is a
certain speci?c antibiotics, a topical solution, ointment, disclosure that a number of antibiotics are used in the
and gel containing erythromycin is used. Also used is a topical treatment of acne vulgaris. A 2% erythromycin
topical solution, gel, and lotion containing clindamycin, base was used in an alcohol-water vehicle. A 0.5%
and a cream containing meclocycline sulfosalicylate (a tetracycline was used in an alcohol-water vehicle which
tetracycline derivative). also contained a penetration-enhancing material, n
Some of the undesirable side effects of orally adminis decyl methyl sulfoxide [C1080]. clindamycin phos
tered antibiotics are abdominal cramps, black tongue, phate was incorporated in an alcohol-water vehicle.
cough, diarrhea, fatigue, irritation of the mouth, loss of Also, 1% clindamycin phosphate was incorporated in a
appetite, nausea, vomiting, fever, hearing loss, jaundice, 40 methyl pyrrolidone vehicle.
rash, rectal and vaginal itching, and superinfection. Also, on page 98, under the subtopic “Penetrant ef
It is noted that erythromycin is produced by the fect of the vehicle” there is a statement that equal parts
bacterium Streptomyces enztheus and that erythromycin of alcohol and water (as well as CwMSO and methyl
has a chemical structure that is substantially unique to pyrrolidone) have a penetrant effect to penetrate the
erythromycin and its derivatives. The molecular weight canal of the sebaceous follicle. There is no mention of
of erythromycin A is 733.92. The empirical formula for any form of a cephalosporin whatsoever. Thus, for
erythromycin A is C37H67NO13 having a 60.55% car fourteen years prior to the Applicants ?ling of the par
bon content, a 9.20% hydrogen content, a 1.91% nitro ent application, the prior art disclosed the use of the
gen content, and a 28.34% oxygen content. topical application of a wide variety of antibiotics to
Clindamycin has a chemical structure indicated by its 50 treat acne using a water/water-miscible alcohol based
chemical name which is methyl 7-chloro-6,7,8-trideoxy carrier that enhances penetration of the antibiotic into
6-[[(l-methyl-4-propyl-2-pyrrolidinyl)carbonyl]amino]
the canal of the sebaceous follicle.
1-thio-L-threo-alpha-D-galacto-octopyranoside. The Heymes (U.S. Pat. No. 4,097,595 patented in 1978)
molecular weight of clindamycin is 424.98. The empiri discloses novel 7-amino-thiazolyl-acetamido-cephalos
cal formula for clindamycin is C1gH337ClN2O5S having 55 poranic acid compounds of the formula (see patent for
a 50.87% carbon content, a 7.83% hydrogen content, a chemical structure) wherein R is selected from the
8.34% chlorine content, a 6.59% nitrogen content, a group consisting of hydrogen and a group easily remov
18.82% oxygen content, and a 7.54% sulfur content. able by acid hydrolysis or hydrogenolysis, R(l)is se
Other topical treatments for acne using antibiotics are lected from the group consisting of alkyl of l to 4 car
described in the following Great Britain patents: neo 60 bon atoms, a 5 member heterocyclic ring and a 5 mem
mycin, G. B. Pat. No. 1,054,124; erythromycin, G. B. ber heterocyclic ring containing a ketone group and A
Pat. No. 1,587,428; and erythromycin. derivatives in is selected from the group consisting of hydrogen, alkali
conjunction with benzoyl peroxide, G. B. Pat. Nos. metal and equivalents of alkaline earth metals, magne
2,088,717 and 2,090,135. sium and organic amine having antibiotic activity
Still another topical treatment for acne, more speci? 65 against gram negative and gram positive bacteria and
cally acne vulgaris, includes preparation of a hyaluronic their preparation and novel intermediates thereof.
acid derivative which is a bridged conjugate of hyalu These cephalosporin derivatives can be applied topi
ronic acid (which is a linear polymer of N-acetyl glu cally to skin for a number of conditions disclosed at
5,409,917
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column 4, lines 27-55. There is no disclosure of the In AHFS Drug Information, 1990, Gerald K.
treatment of acne or other acneiform disorders. The in McEvoy, editor, published by American Society of
vivo examples are only for mice infected by intraperito Hospital Pharmacists, entry on “Cephalosporins”,
neal injection of material containing microorganisms pages 82-87, there is a discussion of cephalosporins and
and subcutaneous administration of the cephalosporin. treatments employing cephalosporins. However, there
In Stoughton et al, “Topical Antibiotic Therapy of is no disclosure of the use of cephalosporins topically.
Acne”, Cutis, 1980, February, 25(2):2l6-218,220, there Still further, there is no topical preparation of cephalo
is a disclosure that a number of vehicles can be used to sporins disclosed. In this respect, there is no disclosure
improve the skin penetrating power of topically applied of the use of cephalosporins to treat acne topically.
antibiotics in the treatment of acne. The antibiotics were In US. Pat. No. 4,444,755 of Horrobin, issued on
applied with their respective vehicles whose penetra Apr. 24, 1984, there is a disclosure that a number of skin
tion was being studied, to hairless mouse skin in vitro. disorders can be treated with gamma-linolenic acid or
The antibiotics that are disclosed as being topically dibromo-gamma-linolenic acid. There is a teaching and
applied to the hairless mouse skin in vitro are erythro claims to the effect that gamma-linolenic acid 'or di
mycin, cephalexin (a cephalosporin), troleandomycin, 5 brorno-gamma-linolenic acid serve to increase prosta
and minocycline. It is noted that on page 220, lines 4-6, glandin(l) activity over prostaglandin(Z) activity for
there is a disclosure that no signi?cant activity was the treatment a large number of skin conditions which
shown by cephalexin in the in vitro skin penetration include acne. Use of a beta-lactam antibiotic (e. g. a
study. cephalosporin) is disclosed, and Horrobin (U.S. Pat.
It is noted in the last footnote on page 218 that Vehi No. 4,444,755) teaches that the purpose of using the
cle 3 in the study was “Vehicle/N TM ” of Neutrogena beta-lactam antibiotic is to enhance utilization of ester
Dermatologics. Vehicle 3 includes ethyl alcohol 47.5%, reserves of dibromo-gamma-linolenic acid (column 5,
puri?ed water, laureth~4, isopropyl alcohol 4%, and lines 63-64). The antibiotic is present in a small amount
propylene glycol. to enhance the activity of the gamma-linolenic acid
In Eady et al, “The Use of Antibiotics in Acne Ther which is present in a large amount. The enhancement of
prostaglandin(l) series compounds is also the purpose of
apy: Oral or Topical Administration?”, J Antimicrob
Chemother, 1982, Aug; 10(2):89-115, there is a disclo zinc, and this would be the purpose of “other materials
sure that tetracycline, erythromycin, chloramphenicol, in?uencing the 1-series/2-series PG balance in the body
co-trimoxazole, and clindamycin are used topically in in favour of l-series PG’s” (column 2, lines 17-19).
the treatment of acne. On page 104, in the second para There is no disclosure of administering a beta-lactam
antibiotic (e. g. a cephalosporin) without concomitant
graph under “Conclusions”, there is a background state
ment that “Penicillins and cephalosporins currently administration of a gamma-linolenic acid or dibromo
gamma-linolenic acid. Thus, for approximately seven
account for 50-65% of total antibiotic usage . . . ”.
years before the Applicants invention, the prior art has
However, there is no teaching that either penicillins or
5 disclosed the use of a small, optional amount of a cepha
cephalosporins are used in the treatment of acne.
losporin to enhance the activity of a large, required
In Witkowski J. A. and Parish, L. C., “Bacterial skin
infections: management of common streptococcal and amount of administered gamma-linolenic acid or di
staphylococcal lesions”, Postgrad Med, October 1982, bromo-gamma-linolenic acid in the treatment of acne.
72 (4), pages 166-8, 171-3, 176-8, and 181-5 in the Research relating to acne has been an active area of
English language, there is a disclosure that penicillin G, 40 investigation for many years. In this respect, many pub
penicillin V, ampicillin, cefaclor (a cephalosporin), lications in the medical literature have been made since
cephalexin (a cephalosporin), cefazolin (a cephalospo the year 1979 to Feb. 12, 1993 (a date of a comprehen
rin), cephradine (a cephalosporin), cloxacillin, diclox sive computer search) relating to acne.
acillin, methicillin, nafcillin, and oxacillin have been More speci?cally, a search of the MEDLINE data
base using Dialog Information Services for articles
used systemically to treat streptococcal and staphylo
mentioning “acne” has revealed that in the time period
coccal infection (see pages 176-177). Use of topical
spanning 1979 through Feb. 12, 1993), there were 2,524
bacitracin, erythromycin, or neomycin is disclosed on
articles. Therefore, for this fourteen year period, there
page 182. Systemic use of penicillin is also mentioned on
page 182. There is no mention of the use of topical was an average of more than 180 articles per year relat
penicillin G, penicillin V, ampicillin, cefaclor ‘(a cepha ing to acne treatment.
losporin), cephalexin (a cephalosporin), cefazolin (a A more speci?c breakdown of a speci?c year versus
cephalosporin), cephradine (a cephalosporin), cloxacil the number of articles relating to acne treatment for that
year is present in the Table as follows:
lin, dicloxacillin, methicillin, nafcillin, or oxacillin to
topically treat streptococcal and staphylococcal infec
tion. Furthermore, there does not appear to be any .
Table of Articles
mention of the treatment of acne, either systemically or
Number of Articles
topically.
Mentioning Acne
In “Cephalosporin for acne vulgaris” [letter], Sheeler
1979 176
R. D., J Am Acad Dermatol, June 1986, 14 (6), page 60 1980 177
1091, there is a disclosure that the cephalosporins, cefo 1981 181
droxil and cefaclor, given orally were effective in re 1982 185
1983 204
ducing lesions of acne vulgaris as a side effect for treat
1984 198 approx. num. before Horrobin: 82
ing other infections. The oral cephalosporin treatment
approx. num. after Horrobin: 116
followed an unsuccessful treatment regimen of using 65 1985 206
systemic tetracycline and topical benzoyl peroxide. 1986 189
1987 182
There is no disclosure of the use of the cephalosporins
1988 200
topically to treat acne. 1989 160
5,409,917
9 10
does not have the risk of bearing a toxic residue of a
-continued
toxic bridging agent.
Table of Articles
In accordance with the invention, a cephalosporin or
Number of Articles
cephalosporin derivative is mixed with a carrier and
Year Mentioning Acne
applied topically to the skin of a patient suffering from
1990 183
acne which includes acne vulgaris and other acneiform
1991 155 approx. num. before Invention: 39
dermal disorders. Suitable cephalosporins include cefa
approx. num. after Invention: 116
1992 128 clor, cefadroxil, cefamandole nafate, cefazolin, ce?x
1993 0 (as of ime, cefmetazole, cefonicid, cefoperazone, ceforanide,
February 12, 1993)
10 cefotanme, cefotaxime', cefotetan, cefoxitin, cefpodox
ime proxetil, ceftazidime, ceftizoxime, ceftriaxone, cef
It is recalled that Horrobin (US. Pat. No. 4,444,755) triaxone moxalactam (a l-oxa-beta-lactam), cefuroxime,‘
was published on Apr. 24, 1984, and the Applicants cephalexin, cephalosporin C cephalosporin C, sodium
parent patent application was ?led Mar. 5, 1991. salt, cephalothin, cephalothin sodium salt, cephapirin,
From the Table of Articles, the following additional cephradine, the 1~acetyloxy ethyl ester of cefuroxime
facts are deduced. From the publication of Horrobin on
(cefuroxime-axetil), dihydratecephalothin, and mox
Apr. 24, 1984 (the prior art that discloses the topical
alactam.
treatment of acne using a cephalosporin and gamma
cephalosporins are deemed in this patent to include
linolenic acid or dibromo-gamma-linolenic acid) to the
cephalosporin derivatives such as carbacephems, and,
?ling of the Applicants parent application on Mar. 5, 20 more speci?cally, loracarbef which is marketed by Eli
1991, approximately 1,275 articles relating to acne were
Lilly Co., Indianapolis, Ind., as lorabid. See The Medi
published in approximately seven years.
cal Letter, Vol. 34, (Issue 879), pages 87-88, Sep. 18,
Therefore, for approximately seven years before the
1992. Moregspeci?cally, loracarbef is chemically identi
Applicants ?led their parent patent application, the
cal to cefaclor except that the sulfur atom in the dihy
prior art (Horrobin (U .8. Pat. No. 4,444,755» disclosed
drothiazone ring has been replaced by a methylene
the use of a primary active ingredient (gamma-linolenic
group to form a tetrahydropyridine ring. See Cooper,
acid or dibromo-gamma-linolenic acid) optionally with
Am. J. Med, Vol. 92, Suppl 6A:2S, Jun. 22, 1992. It is
or without a cephalosporin for the topical treatment of
thought generally that carbacephems have greater
acne. Yet, in spite of the other prior art, such as the
chemical stability in solution. See Pasini et al, Pharm.
Frank reference where an antibiotic (other than a ceph
Res., 9:250, 1992.
alosporin) is the sole active ingredient for topical treat
It is disclosed in the medical literature that some of
ment of acne using a water/water-miscible alcohol car
the cephalosporins have activity in vitro against Propi
rier, only the Applicants provide a method of treating
acne topically with simply a composition consisting onibacterium acnes. However, there is no disclosure of
using a cephalosporin to topically treat acne. More
essentially of a cephalosporin in a carrier which in
speci?cally, the medical literature indicates that the
cludes water and a water-miscible alcohol.
following cephalosporinsare active against Propioni
Moreover, the Horrobin patent does not mention use
of conventional topical anti-acne ingredients selected bacterium acnes in vitro: cefaclor, cefonicid, cefopera
from the group consisting of benzoyl peroxide, sulfur, zone, cefotanme, cefotetan, ceftazidime, ceftizoxime,
resorcinol, salicylic acid, and tretinoin for topical treat 40 ceftriaxone, cefuroxime, and loracarbef.
ment of acne. In this respect, only the Applicants inven It is also contemplated that aztreonam can be used
tion provides for the topical use of a cephalosporin topically for treating acne. Aztreonam is marketed by
along with conventional anti-acne ingredients selected E. R. Squibb and Sons, Inc., Princeton, N.J., under the
from the group consisting of benzoyl peroxide, sulfur, name Azactam TM . Aztreonam is the ?rst of a new class
resorcinol, salicylic acid, and tretinoin. 45 of antibiotics classi?ed as monobactams.
With the invention, a variety of treatment regimens
SUMMARY OF THE INVENTION are contemplated.
Accordingly, it is an object of the invention to pro In a ?rst treatment regimen, topical compositions of
vide a new topical treatment for acne and acneiform the invention are used alone to treat the acne and acnei
dermal disorders. form dermal disorders. In this respect, the topical com
Another object of the invention is to provide a new positions of the invention can be used as a ?rst line
topical treatment for acne which effectively adds to the treatment for acne and acneiform dermal disorders.
arrnamentarium of physicians, and in particular derma In a second treatment regimen of the invention, an
tologists, to treat heretofore resistant forms of acne for orally administered antibiotic and a topical composition
which there was no safe, minimal side effect, and effec 55 of the invention are used in combination. There are a
tive treatment available. number of speci?c courses of treatment that can be
Another object of the invention is to provide a new carried out in this second treatment regimen. The oral
topical treatment for acne which will avoid the undesir antibiotic and the topical composition of the invention
able side effects of the currently available oral antibiot can be administered simultaneously from the beginning.
ics for the systemic treatment of acne and acneiform 60 Or, the oral administration can be begun ?rst, and the
dermal disorders, such as diarrhea, abdominal cramp topical administration can then be begun. The oral ad
ing, nausea, vomiting, drug eruptions, photosensitivity, ministration can continue when the topical administra
blood dyscrasias (e. g. depression of white blood cell tion begins, or the oral administration can stop when the
count and red blood cell count), drug induced hepatitis topical administration begins. Alternatively, the oral
(elevation of liver functions), and teratogenicity, to 65 antibiotic and the topical composition of the invention
name a few. can be administered sequentially. With sequential ad
Still another object of the invention is to provide a ministration, oral administration can take place ?rst,
topical treatment for acne which uses an antibiotic that and then topical administration can be begun.
5,409,917
11 12
In this respect, after a conventional regimen of treat neutrophil and lymphocyte chemotaxis (this refers to
ing a patient for acne or acneiform dermal disorders the attraction of blood cells or biologic products toward
with an orally administered antibiotic, such as tetracy a region of activity), thereby reducing the in?ammatory
cline, minocycline, oxycycline, erythromycin, wherein
in?ltrate and decreasing the lesion of acne. "
the patient develops resistance or no improvement, it is
the teaching of this invention that a cephalosporin is DETAILED DESCRIPTION OF PREFERRED
administered topically to the patient. EMBODIMENTS
In a third treatment regimen of the invention, con It is understood herein that the term cephalosporin
ventional topical medications and topical compositions derivative is a compound that contains the following
of the invention can be administered simultaneously. chemical structural components: 3-[(acetyloxy)methyl]
The conventional topical medications which can be 7-[(R-)amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct
used include: benzoyl peroxide and/or topical Retin 2-ene-2-carboxylic acid, where R is a reactive group
ATM (tretinoin) and/or any other topical agent cur substituted on the nitrogen of the 7-amino group.
rently used by physicians in the treatment of acne and It is noted that for cephalosporin C there is a S-amino
acneiform dermal disorders. 15 5-carboxy-l-oxopentyl group on the nitrogen of the
In a fourth treatment regimen of the invention, con 7-amino group. More speci?cally, for cephalosporin C,
ventional oral medications, conventional topical medi the “R” in the formula for cephalosporin derivatives is
cations, and topical compositions of the invention can a 5-amino-5-carboxy-l-oxopentyl group.
be administered simultaneously. It is noted that for cephalothin there is a 2-thienyl-5
The cephalosporin, or derivative or analog thereof 20 amino-S-carboxy-l-oxopentyl group on the nitrogen of
can be administered alone or in conjunction with a the 7-amino group. More speci?cally, for cephalothin,
nitroimidazole, such as metronidazole, disclosed in US. the “R” in the formula for cephalosporin derivatives is
Pat. No. 4,957,918, incorporated herein by reference. a 5-amino-5-carb0xy-l-oxopentyl group.
Furthermore, the cephalosporin, or derivative or ana Speci?c suitable cephalosporin derivatives are as
log thereof can be applied subsequent to treatment with 25 follows: cephalosporin C; cephalosporin C, sodium salt,
the nitroimidazole compound. dihydrate; cephalothin; cephalothin, sodium salt (also
Although the inventors are not bound by any theoret known as Averon-l, Cefalotin, Cephation, Ceporacin,
ical explanation as to why the compositions and the Cepovenin, Chephalotin, Coaxin, Keflin, Lospoven,
methods of the invention are efficacious in treating acne Microtin, Synclotin, and Toricelocin); cephapirin so
and acneiform dermal disorders, presentation of certain dium; cefadroxil; cefazolin; cephalexin; cephalothin;
theoretical concepts may be of value. cephapin'n; cephradine; cefaclor; cefamandole; cefoni
For one thing, it is felt that the ef?cacy of the compo cid; ceforanide; cefotetan (a cephamycin); cefoxitin (a
sitions and the methods of the invention is due in part to cephamycin); cefuroxime; the l-acetyloxy ethyl ester of
the antibiotic qualities of the compositions employed cefuroxime (cefuroxime axetil and Ceftin); cefopera
and the fact that a portion of the topically applied anti zone; cefotaxime; cefpodoxime proxetil, ceftazidime;
biotic is absorbed by the skin and enters the patient’s ceftizoxime; ceftriaxone; moxalactam (a l-oxa-beta-lac
bloodstream. tam); and loracarbef (lorabid), among others.
Another possible reason for the ef?cacy of the com In addition, analogs of cephalosporin are also suitable
positions and the methods of the invention is that the for topical treatment of acne. These cephalosporin ana
compositions of the invention exert an anti-in?amma logs include: cephalosporin P1; cephamycins; cepharan
tory effect on the cells of the sebaceous gland unit, thine; and cephradine. ,
thereby decreasing production of neutrophils and lym Suitable carriers for the form of cephalosporin or
phocytes which contribute to in?ammation. cephalosporin derivative or cephalosporin analog can
Still another possible reason for the ef?cacy of the be selected from the group of pharmaceutical carriers
topical compositions and methods of the invention is 45 consisting of: a mixture of water and a water-miscible
that the topically applied antibiotic is able to kill micro organic solvent, e. g. a water-miscible alcohol; a petro
organisms that cannot be killed by an orally adminis latum vehicle; a water soluble gel; a mineral oil base; a
tered antibiotic. More speci?cally, the topically applied blend of mineral oil and petrolatum; a suspension of an
antibiotic directly kills microorganisms in the sebaceous ion-exchange resin, e. g. Amberlite, in water; and other
follicle that are shielded by a hydrophobic sebaceous suitable pharmaceutical carriers, well known in the art.
?lm inside the follicle from the effects of an antibiotic in By selection of a suitable vehicle, the cephalosporin
the bloodstream. The bloodstream is essentially an can be administered topically as a solution, a gel, a
aqueous medium, and the hydrophobic sebaceous ?lm lotion, a cream, or an ointment. The cephalosporin can
blocks the antibiotic in the bloodstream, from diffusing also be administered topically using liposomes. The
onto the microorganisms on the other side of the seba cephalosporin can also be administered topically using a
ceous ?lm. However, the microorganism may produce liquid-absorbed wipe material made from ?brous or
products that are fat soluble and are able to cross open-cell foam absorbant material. The cephalosporin
through the sebaceous ?lm and thereby irritate the cells can also be administered topically using a slow, time
lining the sebaceous follicle. Thus, the hydrophobic release patch.
sebaceous ?lm may allow passage, in one direction, of 60 In addition to the form of cephalosporin or cephalo~
irritants from the microorganisms to the follicle walls, sporin derivative or cephalosporin analog that is em
but the hydrophobic sebaceous ?lm prevents passage of ‘ ployed as an active ingredient, another active ingredi
antibiotic in the bloodstream from diffusing across the ent, such as benzoyl peroxide can be used.
hydrophobic sebaceous ?lm in the other direction to the For a topical formulation, in addition to the form of
microorganisms.
65 cephalosporin or cephalosporin derivative or cephalo
Even another possible mechanism of action for the sporin analog, the carrier, and possibly another active
ef?cacy of the compositions and methods of the inven ingredient, the formulation can also include an agent
tion is that the compositions of the invention decrease which enhances penetration of an active ingredient
5,409,917
13 14
through the skin. Exemplary agents which increase skin cefaclor in the following percentages: 0.5%, 1%, 3%,
penetration are disclosed in the following U.S. patents 4%, 5%, and 10%.
all of which are incorporated herein by reference: U.S.
Pat. No. 4,537,776 (a binary combination of N-(hydrox EXAMPLE 2
yethyl)pyrrolidone and a cell~envelope disordering 5 A topical dermatological composition containing
compound); U.S. Pat. No. 4,130,667 (using a sugar ester cefaclor is obtained as follows. Mix the following ingre
in combination with a sulfoxide or phosphine oxide); dients in the amounts speci?ed.
and U.S. Pat. No. 3,952,099 (using sucrose monooleate,
decyl methyl sulfoxide, and alcohol).
Other exemplary materials that increase skin penetra Ingredient Weight Per Cent
tion are surfactants or wetting agents which include the Ethyl alcohol 71.2
following: polyoxyethylene sorbitan mono-oleoate Propylene glycol 26.8
cefaclor 2.0
(Polysorbate 80); sorbitan mono-oleate (Span 80); p
isooctyl polyoxyethylene-phenol polymer (Triton WR
1330); polyoxyethylene sorbitan tri-oleate (Tween 85); The composition in this example contains approxi
dioctyl sodium sulphosuccinate; and sodium sarcosinate mately 2% cefaclor.
(Sarcosyl NL-97); and other pharmaceutically accept Other topical dermatological compositions are pres
able surfactants. ented below.
Although there is not a complete understanding of
20 EXAMPLE 3
the detailed theoretical mechanism upon which the
ef?cacy of the topical dermatological compositions of A formulation employing a water soluble gel as a
the present invention which contain cephalosporins and carrier is obtained as follows. More details of the gel
derivatives are founded, this lack of theoretical under carrier are described in U.S. Pat. No. 4,837,378, incor
porated herein by reference.
standing in no way diminishes the bene?ts derived from
25
employing the compositions and methods of the inven A 30 kilogram batch of a composition of the present
invention containing cefaclor (as 0.75% by weight) is
tion and in no way detracts from the utility of the inven
tion as described herein. prepared as follows. 180 grams of Carbopol 940 TM
(0.6% by weight of the ?nal weight of the composition)
Nevertheless, although not proven conclusively, it is
felt that the topical use of cephalosporin or cephalospo 30 was dissolved in 16.5 liters of distilled water containing
rin derivative or cephalosporin analog of the invention 15 grams of ethylenediaminetetraacetic acid (EDTA)
helps diminish the presence of Propionibacterium acnes, disodium dihydrate. Suf?cient amount of 10 wt % so
dium hydroxide (NaOH) solution is added to bring the
and therefore dirm'nish the effects on acne caused by the
presence of Propionibacterium acnes. pH value to about 5. This aqueous polymer solution is
Furthermore, although not proven conclusively, it is 35 called “Part A”. “Part B” is prepared by mixing 900
felt that the topical use of cephalosporin or cephalospo grams of propylene glycol (3% by weight of the ?nal
rin derivative or cephalosporin analog of the invention weight of the composition), 24 grams of methyl paraben
(0.08% by weight of the ?nal weight of the composi
serves to inhibit the skin’s in?ammatory response. More
speci?cally, it is felt that by using the principles of the tion), and 6.0 grams of propyl paraben (0.02% by
invention, there is a decrease in chemotaxis of lympho weight of the final weight of the composition). The
cytes and neutrophils toward the pilosebaceous unit mixture is added to 225 grams of cefaclor dispersed in
where in?ammation and follicular plugging, and seba 11.4 liters of distilled water maintained at 50 degrees
ceous ?uid are accumulating. It may be that the major Centigrade. Parts A and B are then mixed thoroughly
effect of topical cephalosporins is this anti-chemotactic and gelling of the composition results A cold aqueous
effect of neutrophils and lymphocytes. 45 solution of NaOH is then used to adjust the ?nal pH
A variety of suitable cephalosporin compositions of value to approximately 5.25. Distilled water is then
the invention for topical application to the skin for added to give the desired 30 kilogram ?nal weight. The
treating acne and acneiform dermal disorders are pres NaOH and water are thoroughly mixed into a viscous
ented below in Examples l-156. gel. Other suitable compositions can be made in accor
50 dance with this example which include cefaclor in the
EXAMPLE 1 following percentages: 0.5%, 1%, 2%, 3%,‘4%, 5%,
A topical dermatological composition containing and 10%.
cefaclor is obtained as follows. Mix the following ingre
EXAMPLE 4
dients in the amounts speci?ed.
55 Another topical dermatological gel is obtained by
mixing the following ingredients in suitable amounts:
Ingredient Weight Per Cent allantoin, carbomer 934P, methylparaben, polyethylene
Ethyl alcohol 41.5 glycol 400, propylene glycol, sodium hydroxide, puri
Laureth—4 0.5 ?ed water and cefaclor.
Isopropyl alcohol 6.0
cefaclor 2.0 EXAMPLE 5
Puri?ed water balance
A powdery composition is obtained as follows. Mix
the following ingredients in the amounts speci?ed.
Citric ‘acid can be used to adjust the pH to a desired
level. 65
The composition in this example contains approxi Ingredient Weight Per Cent
mately 2% cefaclor. Other suitable compositions can be
Benzoyl peroxide (micronized) 1 to 35
made in accordance with this example which include Calcium phosphate 63 to 98.5
5,409,917
15 16
-continued -continued
Ingredient Weight Per Cent Weight Per Cent
cefaclor o 5 to 5 in the Final Mixture
' containing antibiotic,
5 benzoyl peroxide, and
Ingredient in gel carrier gel carrier
EXAMPLE 6 Dioctyl sodium sulfosuccinate 1.00
A liquid composition is obtained as follows. Mix the
following ingredients in the amounts speci?ed.
10 EXAMPLE 8
Ingredient weight Per Cam A top1cal_derr_natologtcal gel composition containing
cefaclor ant1b1ot1c and benzoyl peroxlde 1n a gel carrier
cefaclor o‘s '0 5 or vehicle is obtained as follows
Benzoyl peroxide (micronized) 1 to 30 _ ' .
Ethanol The Balance to 100% 15 To a ?rst container add the benzoyl peroxide and the
gel carrier or vehicle ingredients (approximately 5
grams of benzoyl peroxide and approximately 89 grams
EXAMPLE 7 of gel carrier or vehicle). To a second container add
powdered cefaclor (approximately 3 grams of cefaclor).
A topical dermatological composition containing
0 The contents of the ?rst container and the contents of
cefaclor is obtained as follows. Mix the following ingre
the second container are stable for long periods of time.
dients in the amounts speci?ed.
When the topical composition containing cefaclor and
benzoyl peroxide of the invention is to be made, a quan
Ingredient Weight Per Cent tity of 70% ethyl alcohol (e. g. 3 ml.) is added to the
Ethyl alcohol 48.0 25 second container to dissolve the cefaclor and form an
Laureth-4 0.5 alcoholic solution thereof. Then the alcoholic solution
Isopropyl alcohol 4.0 of cefaclor is added to the ?rst container, and all the
Propylene glycol 10.0 ingredients are mixed to form the topical gel composi
cefaclor 1.0
tion of the invention which contains both cefaclor and
Puri?ed water balance
30 benzoyl peroxide. This composition of the invention is
stable, under refrigeration, for approximately 3 months.
Citric acid can be used to adjust the pH to a desired More speci?cally, the blended topical gel composi
level.
tion of the invention with contains cefaclor and benzoyl
The composition in this example contains approxi
peroxide in a gel carrier or vehicle has the following
mately 1% cefaclor. Other suitable compositions can be
35 components in the approximate amounts speci?ed.
made in accordance with this example which include
cefaclor in the following percentages: 0.5%, 2%, 3%,
4%, 5%, and 10%. Ingredient Weight‘Per Cent
For Example 8, reference is made to US. Pat. No.
cefaclor 3.0
4,497,794, incorporated herein by reference, in which Benzoyl peroxide 5.0
topical gel compositions containing the antibiotic eryth Gel carrier or vehicle 92.0
romycin and benzoyl peroxide in a gel carrier are dis
closed. A number of topical gel compositions of the Citric acid can be used to adjust the pH to a desired
present invention can be made by simply replacing the level.
erythromycin disclosed in the gel compositions in said 45 The composition in this example contains approxi
patent with a cephalosporin to provide topical gel com mately 3% cefaclor. Other suitable compositions can be
positions of the invention which contain benzoyl perox made in accordance with this example which include
ide and the respective cephalosporin antibiotic of the cefaclor in the following percentages: 0.5%, 1%, 2%,
invention. 4%, 5%, and 10%.
The gel carrier or vehicle for Example 8, prior to
50
addition of the benzoyl peroxide and prior to addition of EXAMPLE 9
the respective cephalosporin antibiotic of the invention A dermatological lotion containing cefaclor is ob
and, as explained below, the approximately 3 ml. of tained by mixing the following ingredients in the
ethyl alcohol used to dissolve the respective antibiotic amounts speci?ed. The ingredients in Container A is
for addition to the gel carrier to which benzoyl perox blended with the ingredients in Container B.
ide has been added, is comprised of the following ingre
dients in the approximate amounts speci?ed.
Weight Per Cent
of ingredient in
Weight Per Cent Ingredient overall lotion
in the Final Mixture M
containing antibiotic,
Ethoxylated cetyl-stearyl alcohol 7.00
benzoyl peroxide, and
Cetyl alcohol 0.75
Ingredient in gel carrier gel carrier
Isopropyl myristate 5.00
Butylated hydroxyanisole 0.10 Butylated hydroxyanisole 0.10
Colloidal Bentonite 2.50 65 Polyoxyl 40 stearate 0.25
Carboxy vinyl polymer (acid form) 1.00 Water, deionized or distilled 70.80
Water, deionized or distilled 54.65 Propylene glycol 3.00
Diisopropanolamine 0.75 Acetone 7.00
Ethyl alcohol 32.00 Dioctyl sodium sulfosuccinate 0.10
5,409,917
17 18
-continued EXAMPLE 12
Weight Per Cent
A cream composition is obtained as follows. Mix the
of ingredient in
following ingredients in the amounts speci?ed.
Ingredient overall lotion
5
In Container B: i
Acetone 3.00 Ingredient Weight Per Cent
cefaclor 3.00
Ethoxylated cetyl-stearyl alcohol 15
Cetyl alcohol 1.25
Citric acid can be used to adjust the pH to a desired Decyl oleate 5
10
level. Butylated hydroxyanisole 0.10
To obtain the lotion composition in this example, the Polyoxyl 4O stearate 0.25
Water, deionized or distilled 57.30
composition in Container A is prepared. This composi
Propylene glycol 3
tion in Container A is stable for long periods of time. Benzoyl peroxide (micronized) 5
Container B can contain only cefaclor for a long Acetone 10
period of time. Just prior to forming the complete lotion Dioctyl sodium sulphosuccinate 0.1
cefaclor 3
composition, 3 grams of acetone are added to Container
B to dissolve the cefaclor. Then, the contents of Con
tainer A and Container B are combined to form the Other suitable compositions can be made in accor
complete lotion composition of the invention. 20 dance with this example which include cefaclor in the
The composition in this example contains approxi following percentages: 0.5%, 1%, 2%, 4%, 5%, and
mately 3% cefaclor. Other suitable compositions can be 10%.
made in accordance with'Example 62 which include
EXAMPLE 13
cefaclor in the following percentages: 0.5%, 1%, 2%,
4%, 5%, and 10%. 25 A gel composition is obtained as follows. Mix the
following ingredients in the amounts speci?ed.
EXAMPLE 10
A lotion composition is obtained as follows. Mix the
Ingredient Weight Per Cent
following ingredients in the amounts speci?ed.
30 Water, deionized or distilled 51.65
Butylated hydroiiyanisole 0.10
Benzoyl peroxide (micronized) 5
Ingredient * Weight Per Cent
Dioctyl sodium sulphosuccinate 1
Ethoxylated cetyl-stearyl alcohol 7 Colloidal Bentonite 2.5
Cetyl alcohol 0.75 Carboxy vinyl polymer (acid form) 1
Isostearyl neopentanoate 5 35 Ethyl alcohol 35
Butylated hydroxyanisole 0.10 Diisopropanolazine 0.75
Polyoxyl 40 stearate " 0.25 cefaclor 3
Water, deionized or distilled 66.8
Propylene glycol 3
Benzoyl peroxide (micronized) 5 Other suitable compositions can be made in accor
Acetone 10 dance with this example which include cefaclor in the
Dioctyl sodium sulphosuccinate 0.1
following percentages: 0.5%, 1%, 2%, 4%, 5%, and
cefaclor 2
10%.
Other suitable compositions can be made in accor EXAMPLE 14
dance with this example which include cefaclor in the
45 A suspension composition is obtained as follows. Mix
following percentages: 0.5%, 1%, 3%, 4%, 5%, and
the following ingredients in the amounts speci?ed.
10%.
EXAMPLE 11
Ingredient Weight Per Cent
A cream composition is obtained as follows. Mix the
50 Water, deionized or distilled 54.97
following ingredients in the amounts speci?ed. Butylated hydroxyanisole 0.10
Benzoyl peroxide (micronized) , 5
Dioctyl sodium sulphosuccinate 1
Ingredient Weight Per Cent Colloidal Bentonite 1.5
- Carboxy vinyl polymer (acid form) 0.25
Ethoxylated cetyl-stearyl alcohol 15
Cetyl alcohol 1.25 55 Ethyl alcohol 35
Diisopropanolamine 0.18
Isostearyl neopentanoate 5
cefaclor 2
Butylated hydroxyanisole 0.10
Polyoxyl 40 stearate 0.25
Water, deionized or distilled 57.30 Other suitable compositions can be made in accor
Propylene glycol 3
dance with this example which include cefaclor in the
Benzoyl peroxide (micronized) 5
Acetone 10 following percentages: 0.5%, 1%, 3%, 4%, 5%, and
Dioctyl sodium sulphosuccinate 0.1 10%.
cefaclor 3
EXAMPLE 15
Other suitable compositions can be made in accor 65 A dermatological lotion is obtained by mixing the
dance with this example which include cefaclor in the following ingredients in suitable amounts: amoxicillin
following percentages: 0.5%, 1%, 2%, 4%, 5%, and (approximately 1% by weight); and a carrier which
10%. includes isopropyl alcohol (approximately 80% by