Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
  • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

• the present invention relates to the field of treating the skin condition known as acne. More specifically, the present invention is concerned with the prophylactic or therapeutic topical treatment of acne. Even more specifically, the present invention is concerned with the topical treatment of such skin disorders as acne vulgaris, other acneiform dermal conditions, e. g. preadolescent acne, acne rosacea (now known as rosacea) , premenstrual acne, acne venenata, acne cosmetica, pomade acne, acne detergicans, acne cosmetica, acne excoriee, gram negative acne, steroid acne, acne conglobata, or nodulocystic acne.
• the present invention can also be used for topically treating certain types of dermatitis, e. g.
• perioral dermatitis seborrheic dermatitis, gram negative folliculitis, sebaceous gland dysfunction, hiddradenitis suppurativa, pseudo- folliculitis barbae, or folliculitis.
• Acne vulgaris is a common disease which afflicts approximately 90% of all teenagers, and, not uncommonly, affects men and women in their twenties or thirties or may persist in adults for many years.
• Acne vulgaris most commonly occurs on oily areas of the skin with high sebaceous gland concentration.
• the areas of high sebaceous gland concentration are the face, ears, retroauricular areas (e. g. behind the ears), chest, back, and occasionally the neck and upper arms.
• Acneiform eruptions can occur wherever there is a pilosebaceous unit or sebaceous follicle which does include the entire surface of the skin.
• the basic lesion in acne is the comedo commonly known as the blackhead.
• the comedo is created by retention of layers of dead skin known as keratin in the lining of the follicles.
• hyperkeratosis which is thickening or retentative layering of keratin
• sebum which is the lipid-laden product of the sebaceous gland.
• the cells of the sebaceous glands in which sebum originates are the sebocytes.
• the combination of the keratin and the sebum produces a plugging of the mouth or opening of the follicular canal, and papules are formed by inflammation around the comedones (plural of comedo) .
• Acne vulgaris can appear in many clinical varieties. The mildest case manifests comedones on oily skin and is called acne comedo.
• Papular acne is another variety of acne which has many inflammatory papules. This form of acne is common in adolescent skin, but it can be seen in all ages. The papular inflammatory form of acne can progress to an indurated, deeper, and destructive form known as acne indurata. These lesions can produce severe scarring and can be quite deep seated and destructive.
• Steroid acne vulgaris can occur when oral corticosteroids or topical steroids are used and occurs as inflammatory follicular papules.
• oral corticosteroids When oral corticosteroids are ingested, the inflammatory papules are usually sudden in appearance and can cover the chest, back, arm, and face.
• topical corticosteroids are used for more than two weeks, a localized inflammatory papular response can develop which can proceed to a granulomatous chronic reaction known as steroid acne rosacea.
• Premenstrual acne can occur in a large number of menstruating women as a papular and pustular acne vulgaris, approximately one week prior to menstruation. There is a body of evidence that implicates a surge in progesterone as the mediator of premenstrual acne.
• Preadolescent acne is divided into neonatal, infantile, and childhood forms of acne.
• the neonatal form is limited to the first few weeks of life. It usually develops a couple of days after birth. It more commonly afflicts males and reveals transient facial papules and pustules which can clear spontaneously in a few days or weeks.
• the stimulation of neonatal sebaceous glands by circulating maternal progesterone appears to be the cause.
• the acne persists beyond the first month of life, the acne is called infantile acne and can extend into childhood, adolescence, and adult life.
• the childhood acne can result from a persistent infantile acne or can develop de novo after age two.
• This form of acne is uncommon, but it has more of a male predeliction. It is characterized by comedones commonly in groups, papules, pustules, and, rarely, cysts. This condition can extend from a few weeks to several years and can develop into pubertal acne.
• Acne venenata is by definition a comedonal or papular acne which occurs after exposure to chlorinated hydrocarbons (chloracne) , cutting oils, petroleum oil, coal tar, and pitches.
• Acne cosmetica is a persistent low grade comedonal and/or papular and pustular acne that occurs usually on the chin and cheeks of adult women due to oil-based cosmetics, i. e. foundations, facial creams, and sunscreens.
• Pomade acne is a type of acne cosmetica which appears to occur almost exclusively in black persons who apply grease and oil to scalp hair and the face as a grooming aid.
• the lesions are predominately comedonal acne and can develop into inflammatory acne papules, depending upon the chronicity of the pomade use.
• Acne detergicans occurs as a type of comedonal acne in patients who use oil-based cleansing soaps.
• Acne excoriee also known as pickers acne
• pickers acne starts out as mild form of papular or comedonal acne which is manipulated or picked and causes further inflammation, more papules, and sometimes scars, pitting, and atrophy of the skin.
• Gra negative acne sometimes called gram negative folliculitis when it extends to the neck, arms, legs, and truck, is a form of an inflammatory papular, follicular, and pustular response to gram negative organisms including Enterobacter, Klebsiella, Escherichia, Proteus, Serratia, and Pseudomonas.
• the most characteristic lesion on the face is superficial pustules, or papulo-pustules (which is a combination of a papule and pustule) .
• the face can show diffuse erythema and inflammation surrounding these pustules and juicy papules or papulo-pustules.
• the gram negative acne is usually highly resistant and usually occurs in patients who have bad inflammatory papular acne for long periods or who have been treated with long term oral administration of antibiotics such as tetracycline, erythromycin, or minocycline or topical antibiotics such as topical clindamycin or topical erythromycin.
• ampicillin and amoxicillin
• unwanted side effects from oral administration often include diarrhea, cramping, and nausea.
• ampicillin and amoxicillin
• Acne rosacea is an inflammatory eruption that is chronic and occurs on the face, especially on the nose as well as the scalp and neck, in some instances. It is manifested by erythema, pustules, papules, telangiectasia (which is dilation of superficial capillaries) , and hypertrophy of sebaceous glands. The middle portions of the face are most frequently involved.
• the eyes and eyelids are not uncommonly involved and can produce inflammation and infection of the conjunctiva, eyelids, and hypertrophy of the meibomian glands.
• Acne rosacea is often called simply rosacea and is most common in middle aged women and men. Rosacea can go on to form a granulamatous roscea which is characterized by resistant inflammatory papules which when biopsied reveal noncaseating epithelial cell granulomas.
• Pseudofolliculitis barbae is a predominantly male affliction which is characterized by inflammatory papules and pustules on the bearded area of the face most commonly in black persons, but all racial groups can be affected.
• the mechanism is thought to be an inflammatory response to the end of hair (usually curly beard facial hair) into the skin causing a foreign body inflammatory response.
• Folliculitis is an inflammatory reaction around the hair follicule which can be bacterial or nonbacterial in nature.
• folliculitis is caused by gram positive organisms such as Staphylococcus and Streptococcus, and less frequently by gram negative bacteria discussed hereinabove with respect to gram negative folliculitis.
• Perioral dermatitis is a common papular inflammatory eruption which is confined around the mouth. It most commonly afflicts women in their early twenties to middle thirties, but it can be seen in adolescents and more mature adults.
• Hiddradenitis suppurativa is a suppurative (chronic) and cystic disease of apocrine gland regions of the skin, including the axillae, perineal region and groin.
• acne congoblata which is a deep cystic and sinus forming type of acne. This condition is essentially a deep, aggressive form of cystic acne occurring in the apocrine gland regions. Topical administration of clindamycin has been used to treat this form of cystic acne.
• the etiology of acne vulgaris and related disorders as discussed above is not completely known in every detail. However, what is known is that acne, in general, is caused by a plurality of factors. In general, there are four main factors that cause acne: genetics; hormonal activity; bacteria; and the inflammatory response.
• Another causitive factor in acne is the presence of bacteria in the follicular canal. Within the follicular canal are bacteria which are indigenous to the follicular lining. They are anaerobic, gram positive organisms called Proprionibacterium acnes. It is interesting to note that they are present in abundance in pathologically affected sites. They are reduced during oral antimicrobial treatment, and their absence from nonhuman animal skin is striking especially since animals do not exhibit acne vulgaris. Yet another causitive factor in acne is the inflammatory response manifested in the skin. More specifically, it is thought that Proprionibacterium acnes lives in symbiosis on the keratin lined follicular canal.
• Proprionibacterium acnes ingests the sebum produced from the sebocytes of the sebaceous glands. This nascent sebum is largely lipid in composition and also contains DNA, RNA, proteins, and other cellular components that result from the breakdown of sebocytes themselves.
• the Proprionibacterium acnes which are highly lipophilic, feed on the nascent sebum. It has been shown that Proprionibacterium acnes are found only in sebaceous rich areas. If the nutrients increase due to an active and large sebaceous system, then colonization and high growth rates of Proprionibacterium acnes will form.
• the resident bacterial flora will produce biologically active molecules such as hista ine, extracellular enzymes, and peptides which may be responsible for the chemotaxis of the inflammatory infiltrate in acne vulgaris. Since the follicular lining in the pilosebaceous unit is intact, it has been theorized that if colonization of Proprionibacterium acnes occurs in sufficent numbers, they could produce initiating antigenic molecules that promote the initiation of inflammation. Proprionibacterium acnes can produce proteinases, lipase, and hyaluronate lyase all of which may serve as the catalysts or initiators of the inflammatory infiltrate which has been shown to be composed of neutrophils and lymphocytes.
• a number of treatments are presently known for treating acne, some more successful than others. Some modes of treatment have been mentioned above. There are two modes of treatment, topical and systemic.
• topical treatments that are presently employed are: topical erythromycin, clindamycin, benzoyl peroxide, 2% sulfur, 3% resorcinol, a tetracycline derivative (meclocycline sulfosalicylate 1%) , 2% salicylic acid, and tretinoin (Retin-A TR) .
• Topical treatments that have been suggested in the past and that are no longer generally employed include: x-ray treatment; electric sparks; vitamin therapy; treatment with a plant extract as described in U. S. Patent No. 4,803,069.
• a topical solution, ointment, and gel containing erythromycin is used.
• a topical solution, gel, and lotion containing clindamycin, and a cream containing meclocycline ⁇ ulfosalicylate 1% (a tetracycline derivative) is used.
• Some of the undesirable side effects of orally administered antibiotics are abdominal cramps, black tongue, cough, diarrhea, fatigue, irritation of the mouth, loss of appetite, nausea, vomiting, fever, hearing loss, jaundice, rash, rectal and vaginial itching, and superinfection.
• erythromycin is produced by the bacterium Streptomvces ervtheus and that erythromycin has a chemical structure that is substantially unique to erythromycin and its derivatives.
• the molecular weight of erythromycin A is 733.92.
• the empirical formula for erythromycin A is C 37 H 67 N0 13 having a 60.55% carbon content, a 9.20% hydrogen content, a 1.91% nitrogen content, and a 28.34% oxygen content.
• Clindamycin has a chemical structure indicated by its chemical name which is methyl 7- chloro-6,7,8-trideoxy-6-[[(l-methyl-4-propyl-2- pyrrolidinyl)carbonyl]amino]-1-thio-L—threo- alpha-D-galacto-octopyranoside.
• the molecular weight of clindamycin is 424.98.
• the empirical formula for clindamycin is C 18 H 337 C1N 2 0 5 S having a 50.87% carbon content, a 7.83% hydrogen content, a 8.34% chlorine content, a 6.59% nitrogen content, a 18.82% oxygen content, and a 7.54% sulfur content.
• Still another topical treatment for acne includes preparation of a hyaluronic acid derivative which is a bridged conjugate of hyaluronic acid (which is a linear polymer of N-acetyl glucosamine and glucuronic acid units) bonded to a bridging agent (which is cyanogen bromide) which, in turn, is bonded to the amino-nitrogen atom of the aminopenicillin, ampicillin.
• a hyaluronic acid derivative which is a bridged conjugate of hyaluronic acid (which is a linear polymer of N-acetyl glucosamine and glucuronic acid units) bonded to a bridging agent (which is cyanogen bromide) which, in turn, is bonded to the amino-nitrogen atom of the aminopenicillin, ampicillin.
• a hyaluronic acid derivative which is a bridged conjugate of hyaluronic acid (which is a linear polymer of N-acetyl gluco
• the formulation disclosed in Great Britain Published Application 2,207,142 poses several significant problems.
• all of the aminopenicillins that are approved for prescribing in the practice of medicine in the United States include an amino-nitrogen which is in the form of a primary amino group (the nitrogen atom of the primary amino group being bonded to two hydrogen atoms) . Not one of these approved aminopenicillins has its characteristic primary a ino group modified so that it is no longer a primary amino group.
• Cyanogen bromide can cause toxic effects similar to those of hydrogen cyanide. Hydrogen cyanide may cause death from only a few minutes exposure to a concentration of approximately 300 ppm. Lesser concentrations may cause headache, vertigo, nausea, and vomiting. With these potentially serious toxic side effects of cyanogen bromide, it would be very risky to even employ the hyaluronic derivative disclosed in Great Britain Published Application 2,207,142.
• an object of the invention to provide a new topical treatment for acne and acneiform dermal disorders.
• Another object of the invention is to provide a new topical treatment for acne which effectively adds to the armamentarium of physicians, and in particular dermatologists, to treat heretofore resistant forms of acne for which there was no safe, minimal side effect, and effective treatment available.
• Another object of the invention is to provide a new topical treatment for acne which will avoid the undesirable side effects of the currently available oral antibiotics for the systemic treatment of acne and acneiform dermal disorders, such as diarrhea, abdominal cramping, nausea, vomiting, drug eruptions, photosensitvity, blood dyscrasias (e. g. depression of white blood cell count and red blood cell count) , drug induced hepatitis (elevation of liver functions) , and teratogenicity, to name a few.
• Another object of the invention is to provide a topical treatment for acne which uses an aminopenicillin whose characteristic amino group is in the form of a primary amino group.
• Still another object of the invention is to provide a topical treatment for acne which uses an antibiotic that does not have the risk of bearing a toxic residue of a toxic bridging agent.
• aminopenicillin is understood to be an aminopenicillin whose characteristic amino group is in the form of a primary amino group.
• cephalosporin or cephalosporin derivative is mixed with a carrier and applied topically to the skin of a patient suffering from acne and other acneiform dermal disorders.
• Suitable cephalosporins include cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephradine, cefaclor, cefamandole, cefonicid, ceforanide, cefotetan (a cephamycin) , cefoxitin (a cephamycin) , cefuroxi e, the 1-acetyloxy ethyl ester of cefuroxime (cefuroxime axetil) , cefoperazone, cefotaxime, ceftazidime, ceftin, ceftizoxime, ceftriaxone, and moxalactam (a 1-oxa- beta-lactam) .
• topical compositions of the invention are used alone to treat the acne and acneiform dermal disorders.
• the topical compositions of the invention can be used as a first line treatment for acne and acneiform dermal disorders.
• an orally administered antibiotic and a topical composition of the invention are used in combination.
• the oral antibiotic and the topical composition of the invention can be administered simultaneously from the beginning.
• the oral adminstation can be begun first, and the topical administration can then be begun.
• the oral administration can continue when the topical administration begins, or the oral administration can stop when the topical administration begins.
• the oral antibiotic and the topical composition of the invention can be administered sequentially. With sequential administration, oral administration can take place first, and then topical administration can be begun.
• an orally administered antibiotic such as tetracycline, inocycline, doxycycline, erythromycin, wherein the patient develops resistance or no improvement
• an antibiotic selected from the group consisting of ampicillin, amoxicillin, another aminopenicillin, penicillin-like derivatives, and cephalosporin, and derivatives and analogs thereof, is administered topically to the patient.
• conventional topical medications and topical compositions of the invention can be administered simultaneously.
• the conventional topical medications which can be used include: benzoyl peroxide and/or topical Retin-A (TM) (tretinoin) and/or any other topical agent currently used by physicians in the treatment of acne and acneiform dermal disorders.
• TM topical Retin-A
• conventional oral medications, conventional topical medications, and topical compositions of the invention can be administered simultaneously.
• a treatment for ocular rosacea, blepharitis, blepharoconjunctivitis, giant papillary conjunctivitis, meibo ian gland dysfunction, and infection by Acanthamoeba organisms is provided by topically administering to the eyelids and/or eyeballs a composition containing an ampicillin, amoxicillin, another aminopenicillin, other penicillin-like derivative, a cephalosporin, or derivative or analog thereof, and a suitable ophthalmological carrier selected from the group consisting of an aqueous liquid, an artificial tear solution, a water soluble gel, an ointment base, petrolatum, a nonaqueous liquid base, a mineral oil base, a blend of mineral oil and petroleum, a suspension of solid particles in a liquid, and a suspension of an ion-exchange resin in water.
• ampicillin, amoxicillin, another aminopenicillin, or other penicillin-like derivative, cephalosporin, or derivative or analog thereof can be administered alone or in conjunction with a nitroimidazole, such as metronidazole, disclosed in U. S. Patent No. 4,957,918, incorporated herein by reference. Furthermore, the ampicillin, amoxicillin, another aminopenicillin, or other penicillin-like derivative, cephalosporin, or derivative or analog thereof can be applied subsequent to treatment with the nitroimidazole compound.
• a nitroimidazole such as metronidazole
• compositions and the methods of the invention are efficacious in treating acne and acneiform dermal disorders
• presentation of certain theoretical concepts may be of value.
• efficacy of the compositions and the methods of the invention is due in part to the antibiotic qualities of the compositions employed and the fact that a portion of the topically applied antibiotic is absorbed by the skin and enters the patient's bloodstream.
• compositions of the invention exert an anti-inflammatory effect on the cells of the sebaceous gland unit, thereby decreasing production of neutrophils and lymphocytes which contribute to inflammation.
• the topically applied antibiotic is able to kill microorganisms that cannot be killed by an orally administered antibiotic. More specifically, the topically applied antibiotic directly kills microorganisms in the sebaceous follicle that are shielded by a hydrophobic sebaceous film inside the follicle from the effects of an antibiotic in the bloodstream.
• the bloodstream is essentially an aqueous medium, and the hydrophobic sebaceous film blocks the antibiotic in the bloodstream, from diffusing onto the microorganisms on the other side of the sebaceous film.
• the microorganism may produce products that are fat soluble and are able to cross through the sebaceous film and thereby irritate the cells lining the sebaceous follicle.
• the hydrophobic sebaceous film may allow passage, in one direction, of irritants from the microorganisms to the follicle walls, but the hydrophobic sebaceous film prevents passage of antibiotic in the bloodstream from diffusing across the hydrophobic sebaceous film in the other direction to the microorganisms.
• penicillin-like derivative is a compound that contains the following chemical structural components: 6-[R-carbonyl)amino]-3,3-di-methyl-7- oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid, where R is a reactive group substituted on the carbonyl carbon on the nitrogen atom of the 6- amino group.
• Ampicillin is an aminopenicillin.
• aminopenicillins are semisynthetic penicillin derivatives produced by acylation of 6- aminopenicillanic acid (6-APA) .
• Aminopenicillins have a free amino group (a primary amino group) at the alpha-position on the penicillin nucleus which results in enhanced activity against gram-negative bacteria compared with natural penicillins and penicillinase-resistant penicillins. It is noted that for ampicillin there is a benzylamine group on the carbonyl carbon on the nitrogen atom of the 6-amino group. More specifically, for ampicillin, the "R" in the formula for penicillin-like derivatives is a benzylamine group.
• the R group includes a carbon atom bonded to the carbonyl- amino carbon atom, where a primary amino group is bonded to that carbon atom bonded to the carbonyl- amino carbon atom.
• ampicillin examples include the terms ampicillin A, BRL 1341, P 50, Ay 6108, Adobacillin, Ave, Amfipen, Ampi-Bol, Bonapicillin, Grampenil, Guicitrina, Copharcilin, Nuvapen, Synpenin, Viccillin, Ultrabion, Ampipenin, Amplisom, Amimed, Ampy-Penyl, Totalciclina, A ipenix S, Amblosin, Ampicin, Amplital, Austrapen, Binotal, Britacil, Doktacillin, Marsilan, Pen-Bristol, Penbritin, Penbrock, Penicline, Pentrex, Pentrexyl, Ponecil, Polycillin, QI Damp, Toliocillin, Totacillin, and Totapen.
• Amoxicillin is another aminopenicillin. It is also noted that for amoxicillin there a 4- hydroxybenzylamine group substituted on the carbonyl carbon on the nitrogen atom of the 6- amino group. More specifically, for amoxicillin the "R" in the formula for penicillin-like derivatives is a 4-hydroxybenzylamine group.
• amoxicillin examples include the terms amoxycillin, AMPC, A olin, Amopenixin, Amoxi, A oxipen, Anemolin, Aspenil, Brista ox,
• ampicillin and amoxicillin include “R” groups comprised of benzylamine and 4-hydroxybenzylamine groups, respectively. More generically, in accordance with the invention, compositions containing penicillin-like derivatives where "R” in the formula above is benzylamine and derivatives thereof. Stated somewhat differently, compositions of the invention and the use thereof include ampicillin and derivatives thereof and amoxicillin and derivatives thereof. Also, the compositions of the invention and the use thereof include ampicillin, amoxicillin, or pharmaceutically acceptable salts or solvates thereof.
• Suitable forms of ampicillin and amoxicillin can be selected from the group consisting of ampicillin; ampicillin, monohydrate; ampicillin, potassium salt; ampicillin, sesquihydrate; ampicillin, trihydrate; ampicillin, anhydrous form; ampicillin, sodium salt; ampicillin, D(- )form, L(+)form, or DL-form; other suitable ampicillin derivatives; amoxicillin; amoxicillin trihydrate; amoxicillin hydrochloride trihydrate; amoxicillin beta-naphthalenesulfonate trihydrate; and other suitable amoxicillin derivatives.
• Other suitable aminopenicillins include bacampicillin and cyclacillin.
• Suitable forms of other penicillin-like derivatives or analogs can be selected from the group consisting of azlocillin; acylureido penicillins related to azlocillin; carbenicillin; carbenicillin, disodium salt; carbenicillin, indenyl; cloxacillin; dicloxacillin; dicloxacillin, sodium salt; floxacillin; isoxazolyl penicillins; hetacillin; methicillin; methicillin, sodium; mezlocillin; mezlocillin, sodium salt; nafcillin oxacillin; oxacillin, sodium salt; penicillin BT; penicillin BT, procaine salt; penicillin G; penicillin G benethamine; penicillin G benzathine; penicillin G benzhydrylamine; penicillin G calcium; penicillin G hydrabamine; penicillin G potassium; penicillin G procaine; penicillin N; penicillin N, barium salt; penicillin
• Ampicillin has a chemical structure indicated by its chemical name which is 6- [(aminophenylacetyl)amino]-3,3-di-methyl-7-oxo-4- thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.
• the molecular weight of ampicillin is 349.42.
• the empirical formula for ampicillin is C 16 H 19 N 3 0 4 S having a 55.0% carbon content, a 5.48% hydrogen content, a 12.02% nitrogen content, a 18.32% oxygen content, and a 9.18% sulfur content.
• Amoxicillin has a chemical structure indicated by its chemical name which is 6- [[amino(4-hydroxyphenyl)acetyl]amino]-3,3- dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane- 2-carboxylic acid.
• the molecular weight of amoxicillin is 365.41.
• the empirical formula for amoxicillin is C 16 H 19 N 3 0 5 S having a 52.59% carbon content, a 5.24% hydrogen content, a 11.50% nitrogen content, a 21.89% oxygen content, and a 8.77% sulfur content.
• cephalosporin derivative is a compound that contains the following chemical structural components: 3-[(acetyloxy)methyl]-7-[ (R-)amino]- 8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid, where R is a reactive group substituted on the nitrogen of the 7-amino group. It is noted that for cephalosporin C there is a 5-amino-5-carboxy-l-oxopentyl group on the nitrogen of the 7-amino group.
• the "R” in the formula for cephalosporin derivatives is a 5-amino-5-carboxy- 1-oxopentyl group. It is noted that for cephalothin there is a 2-thienyl5-amino-5-carboxy-l-oxopentyl group on the nitrogen of the 7-amino group. More specifically, for cephalothin, the "R” in the formula for cephalosporin derivatives is a 5- amino-5-carboxy-l-oxopentyl group.
• cephalosporin derivatives are as follows: cephalosporin C; cephalosporin C, sodium salt, dihydrate; cephalothin; cephalothin, sodium salt (also known as Averon-1, Cefalotin, Cephation, Ceporacin, Cepovenin, Chephalotin,
• cephalosporin analogs of cephalosporin are also suitable for topical treatment of acne.
• cephalosporin analogs include: cephalosporin P_,; cephamycins; cepharanthine; and cephradine.
• Suitable carriers for the form of ampicillin, amoxicillin, or other penicillin-like derivative or cephalosporin or cephalosporin derivative or cephalosporin analog can be selected from the group consisting of: a petrolatum vehicle; a water soluble gel; a mineral oil base; a blend of mineral oil and petrolatum; a suspension of an ion-exchange resin, e. g. Amberlite, in water; and other suitable pharmaceutical carriers, well known in the art.
• the ampicillin, amoxicillin, cephalosporin etc. can be administered topically as a solution, a gel, a lotion, a cream, or an ointment.
• a suitable vehicle By selection of a suitable vehicle, the ampicillin, amoxicillin, cephalosporin etc. can be administered topically as a solution, a gel, a lotion, a cream, or an ointment.
• another active ingredient such as benzoyl peroxide can be used.
• the carrier in addition to the form of ampicillin, amoxicillin, another aminopenicillin, or other penicillin-like derivative, or cephalosporin or cephalosporin derivative or cephalosporin analog, the carrier, and possibly another active ingredient, the formulation can also include an agent which enhances penetration of an active ingredient through the skin.
• agents which enhance skin penetration are disclosed in the following U. S. patents all of which are incorporated herein by reference: U. S. Patent No. 4,537,776 (a binary combination of N-(hydroxyethyl)pyrrolidone and a cell-envelope disordering compound) ; U. S. Patent No.
• surfactants or wetting agents which include the following: polyoxyethylene sorbitan mono-oleoate (Polysorbate 80) ; sorbitan mono-oleate (Span 80) ; p-isooctyl polyoxyethylene- phenol polymer (Triton WR-1330) ; polyoxyethylene sorbitan tri-oleate (Tween 85) ; dioctyl sodium sulphosuccinate; and sodium sarcosinate (Sarcosyl NL-97) ; and other pharmaceutically acceptable surfactants.
• surfactants or wetting agents which include the following: polyoxyethylene sorbitan mono-oleoate (Polysorbate 80) ; sorbitan mono-oleate (Span 80) ; p-isooctyl polyoxyethylene- phenol polymer (Triton WR-1330) ; polyoxyethylene sorbitan tri-oleate (Tween 85) ; dioctyl sodium sulphos
• the topical use of ampicillin, amoxicillin, another aminopenicillin, and other penicillin-like derivatives or cephalosporin or cephalosporin derivative or cephalosporin analog of the invention serves to inhibit the skin's inflammatory response. More specifically, it is felt that by using the principles of the invention, there is a decrease in chemotaxis of lymphocytes and neutrophils toward the pilosebaceous unit where inflammation and follicular plugging, and sebaceous fluid are accumulating. It may be that the major effect of topical ampicillin and amoxicillin is this anti- che otactic effect of neutrophils and lymphocytes.
• Example l A topical dermatological composition containing ampicillin is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent Ethyl alcohol 42.0
• Purified water 49.5 Citric acid can be used to adjust the pH to a desired level.
• Example 1 contains approximately 2% ampicillin.
• compositions can be made in accordance with Example 1 which include ampicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing amoxicillin is obtained as follows. Mix the following ingredients in the amounts specified.
• Purified water 49,5 Citric acid can be used to adjust the pH to a desired level.
• Example 2 contains approximately 2% amoxicillin.
• Other suitable compositions can be made in accordance with Example 2 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• Example 3 A topical dermatological composition containing ampicillin is obtained as follows.
• Example 3 contains approximately 2% ampicillin.
• a topical dermatological composition containing amoxicillin is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• Example 4 contains approximately 2% amoxicillin.
• compositions can be made in accordance with Example 4 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a formulation employing a water soluble gel as a carrier is obtained as follows. More details of the gel carrier are described in U. S. Patent No. 4,837,378, incorporated herein by reference.
• a 30 kilogram batch of a composition of the present invention containing ampicillin (as 0.75% by weight) is prepared as follows. 180 grams of Carbopol 940 (TM) (0.6% by weight of the final weight of the composition) was dissolved in 16.5 liters of distilled water containing 15 grams of ethylenediaminetetraacetic acid (EDTA) disodium dihydrate. Sufficient amount of 10 wt% sodium hydroxide (NaOH) solution is added to bring the pH value to about 5. This aqueous polymer solution is called "Part A”.
• Part B is prepared by mixing 900 grams of propylene glycol (3% by weight of the final weight of the composition) , 24 grams of methyl paraben (0.08% by weight of the final weight of the composition), and 6.0 grams of propyl paraben (0.02% by weight of the final weight of the composition) . The mixture is added to 225 grams of ampicillin dispersed in 11.4 liters of distilled water maintained at 50 degrees Centrigrade. Parts A and B are then mixed thoroughly and gelling of the composition results. A cold aqueous solution of NaOH is then used to adjust the final pH value to approximately 5.25. Distilled water is then added to give the desired 30 kilogram final weight. The NaOH and water are thoroughly mixed into a viscous gel.
• compositions can be made in accordance with Example 5 which include ampicillin in the following percentages: 0.5%, 1%, 2%, 3%, 4%, 5%, and 10%.
• a formulation employing a water soluble gel as a carrier is obtained as follows. More details of the gel carrier are described in U. S. Patent
• a 30 kilogram batch of a composition of the present invention containing amoxicillin (as 0.75% by wei»ght) is prepared as follows. 180 grams of Carbopol 940 (TM) (0.6% by weight of the final weight of the composition) was dissolved in 16.5 liters of distilled water containing 15 grams of ethylenediaminetetraacetic acid (EDTA) disodium dihydrate. Sufficient amount of 10 wt% sodium hydroxide (NaOH) solution is added to bring the pH value to about 5. This aqueous polymer solution is called "Part A".
• Part B is prepared by mixing 900 grams of propylene glycol (3% by weight of the final weight of the composition) , 24 grams of methyl paraben (0.08% by weight of the final weight of the composition), and 6.0 grams of propyl paraben (0.02% by weight of the final weight of the composition) . The mixture is added to 225 grams of amoxicillin dispersed in 11.4 liters of distilled water maintained at 50 degrees Centrigrade. Parts A and B are then mixed thoroughly and gelling of the composition results. A cold aqueous solution of NaOH is then used to adjust the final pH value to approximately 5.25. Distilled water is then added to give the desired 30 kilogram final weight. The NaOH and water are thoroughly mixed into a viscous gel.
• compositions can be made in accordance with Example 6 which include amoxicillin in the following percentages: 0.5%, 1%, 2%, 3%, 4%, 5%, and 10%.
• Another topical dermatological gel is obtained by mixing the following ingredients in suitable amounts: allantoin, carbomer 934P, methylparaben, polyethylene glycol 400, propylene glycol, sodium hydroxide, purified water and ampicillin.
• Another topical dermatological gel is obtained by mixing the following ingredients in suitable amounts: allantoin, carbomer 934P, methylparaben, polyethylene glycol 400, propylene glycol, sodium hydroxide, purified water and amoxicillin.
• a dermatological lotion is obtained by mixing the following ingredients in the amounts specified:
• Ampicillin 2 Other suitable compositions can be made in accordance with Example 9 which include ampicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• Example 10 A dermatological lotion is obtained by mixing the following ingredients in the amounts specified:
• compositions can be made in accordance with Example 10 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a powdery composition is obtained as follows. Mix the following ingredients in the amounts specified.
• a liquid composition is obtained as follows. Mix the following ingredients in the amounts specified.
• a topical dermatological composition containing ampicillin is obtained as follows. Mix the following ingredients in the amounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• Example 13 contains approximately 2% ampicillin.
• Example 14 Other suitable compositions can be made in accordance with Example 13 which include ampicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• Example 14
• a lotion composition is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• compositions can be made in accordance with Example 14 which include ampicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a cream composition is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• compositions can be made in accordance with Example 15 which include ampicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a gel composition is obtained as follows. Mix the following ingredients in the amounts specified.
• compositions can be made in accordance with Example 16 which include ampicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a suspension composition is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent Water, deionized or distilled 54.97
• compositions can be made in accordance with Example 17 which include ampicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a powdery composition is obtained as follows.
• a liquid composition is obtained as follows. Mix the following ingredients in the amounts specified.
• a lotion composition is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• Amoxicillin 2 Other suitable compositions can be made in accordance with Example 20 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• Example 21 A cream composition is obtained as follows. Mix the following ingredients in the amounts specified.
• Amoxicillin 3 Other suitable compositions can be made in accordance with Example 21 which include amoxicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• Example 22
• a gel composition is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• Amoxicillin 3 Other suitable compositions can be made in accordance with Example 22 which include amoxicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• pyam le 23 A suspension composition is obtained as follows. Mix the following ingredients in the amounts specified.
• compositions can be made in accordance with Example 23 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• An oil-in-water emulsion containing ampicillin in ointment form is obtained as follows.
• Part A is comprised of a 3.33% aqueous solution of ampicillin.
• Part B is an ointment base comprised of: Ingredient Weight Per Cent viscid paraffin 35 white vaseline 35 cetylstearyl alcohol 30
• a mixture is obtained as follows. Mix 60 ml. of Part A is mixed with 40 ml. of Part B to provide an oil-in-water emulsion in ointment form containing approximately 2% ampicillin.
• compositions can be made in accordance with Example 24 which include ampicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a mineral-oil-based ampicillin ointment is obtained as follows. Part A is comprised of a 6.66% aqueous solution of ampicillin.
• Part B is an ointment base comprised of: Ingredient Parts glycerin 5 isopropyl alcohol, 96% 5 mineral oil 60
• a mixture is obtained as follows. Mix 30 ml. of Part A with 70 ml. of Part B to provide a mineral-oil-based ointment containing approximately 2% ampicillin.
• compositions can be made in accordance with Example 25 which include ampicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• the known densities of water, isopropyl alcohol, glycerin, and mineral oil are employed.
• the known density of water is approximately 1 g/ml.
• the known density of water is approximately 0.78 g/ml.
• the known density of glycerin is approximately 1.25 g/ml.
• the known density of mineral oil is approximately 0.85 g/ml.
• the weight of the 30 ml. of part A is approximately 30 grams, in view of the fact that part A is predominantly water. By taking 30 ml. of part A, approximately 2 grams of antibiotic (30 g. X 6.66% and approximately 28 grams of water (30 g. X 93.34%) are obtained.
• the total weight of parts A and B combined is approximately 91.15 grams (30 g. + 61.15 g.) .
• the weight percents of the individual carrier components are as approximately as follows: water, 31%; isopropyl alcohol, 4.3%; glycerin. 6.86%; and mineral oil, 55.95%. It is noted that the combined weight percentages of the water- miscible alcohols is approximately 11.2% (4.3% + 6.86%). It is also noted that the combined weight perentages of the water and water-miscible alcohols is approximately 42.2% (31% + 11.2%).
• a topical dermatological composition containing cephalosporin C is obtained as follows.
• Citric acid can be used to adjust the pH to a desired level.
• the composition in Example 26 contains approximately 1% Cephalosporin C.
• compositions can be made in accordance with Example 26 which include Cephalosporin C in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing cephalosporin C is obtained as follows.
• Cephalosporin C 2.0 The composition in Example 27 contains approximately 2% cephalosporin C.
• Example 28 A formulation employing a water soluble gel as a carrier is obtained as follows. More details of the gel carrier are described in U. S. Patent No. 4,837,378, incorporated herein by reference.
• a 30 kilogram batch of a composition of the present invention containing cephalosporin C (as 0.75% by weight) is prepared as follows. 180 grams of Carbopol 940 (TM) (0.6% by weight of the final weight of the composition) was dissolved in 16.5 liters of distilled water containing 15 grams of ethylenediaminetetraacetic acid (EDTA) disodium dihydrate. Sufficient amount of 10 wt% sodium hydroxide (NaOH) solution is added to bring the pH value to about 5. This aqueous polymer solution is called "Part A”.
• Part B is prepared by mixing 900 grams of propylene glycol (3% by weight of the final weight of the composition) , 24 grams of methyl paraben (0.08% by weight of the final weight of the composition), and 6.0 grams of propyl paraben (0.02% by weight of the final weight of the composition) .
• the mixture is added to 225 grams of cephalosporin C dispersed in 11.4 liters of distilled water maintained at 50 degrees Centrigrade. Parts A and B are then mixed thoroughly and gelling of the composition results.
• a cold aqueous solution of NaOH is then used to adjust the final pH value to approximately 5.25. Distilled water is then added to give the desired 30 kilogram final weight. The NaOH and water are thoroughly mixed into a viscous gel.
• compositions can be made in accordance with Example 28 which include cephalosporin C in the following percentages: 0.5%, 1%, 2%, 3%, 4%, 5%, and 10%.
• Another topical dermatological gel is obtained by mixing the following ingredients in suitable amounts: allantoin, carbomer 934P, methylparaben, polyethylene glycol 400, propylene glycol, sodium hydroxide, purified water and cephalosporin C.
• a dermatological lotion containing ampicillin is obtained by mixing the following ingredients in the amounts specified. The ingredients in
• Container A is blended with the ingredients in Container B.
• Citric acid can be used to adjust the pH to a desired level.
• the composition in Container A is prepared. This composition in Container A is stable for long periods of time.
• Container B can contain only ampicillin for a long period of time. Just prior to forming the complete lotion composition, 3posins of acetone are added to Container B to dissolve the ampicillin. Then, the contents of Container A and Container B are combined to form the complete lotion composition of the invention.
• Example 30 contains approximately 3% ampicillin.
• compositions can be made in accordance with Example 30 which include ampicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a powdery composition is obtained as follows.
• a liquid composition is obtained as follows. Mix the following ingredients in the amounts specified.
• a lotion composition is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent Ethoxylated cetyl-stearyl alcohol 7
• compositions can be made in accordance with Example 33 which include cephalosporin C in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• Example 34 A cream composition is obtained as follows. Mix the following ingredients in the amounts specified.
• compositions can be made in accordance with Example 34 which include cephalosporin C in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a gel composition is obtained as follows. Mix the following ingredients in the amounts specified.
• Cephalosporin C 3 Other suitable compositions can be made in accordance with Example 35 which include cephalosporin C in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a suspension composition is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent Water, deionized or distilled 54.97
• compositions can be made in accordance with Example 36 which include cephalosporin C in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing amoxicillin is obtained as follows. Mix the following ingredients in the amounts specified.
• Purified water 49,5 Citric acid can be used to adjust the pH to a desired level.
• Example 37 contains approximately 2% amoxicillin.
• Other suitable compositions can be made in accordance with Example 37 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• Example 38 A topical dermatological composition containing ceftin is obtained as follows. Mix the following ingredients in the amounts specified.
• Purified water balance Citric acid can be used to adjust the pH to a desired level.
• Example 38 contains approximately 1% Ceftin.
• Example 37 Other suitable compositions can be made in accordance with Example 38 which include Ceftin in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• Example 37
• a dermatological lotion is obtained by mixing the following ingredients in suitable amounts: ampicillin (approximately 1% by weight) ; and a carrier which includes isopropyl alcohol (approximately 80% by weight) , purified water (approximately 9% by weight) , and propylene glycol (approximately 10% by weight) .
• a dermatological lotion is obtained by mixing the following ingredients in suitable amounts: amoxicillin (approximately 1% by weight) ; and a carrier which includes isopropyl alcohol (approximately 80% by weight) , purified water (approximately 9% by weight) , and propylene glycol (approximately 10% by weight) .
• a dermatological lotion is obtained by mixing the following ingredients in suitable amounts: cephalosporin C (approximately 1% by weight) ; and a carrier which includes isopropyl alcohol
• Example 42 A topical dermatological composition containing cephalexin is obtained as follows.
• Purified water balance Citric acid can be used to adjust the pH to a desired level.
• the composition in Example 42 contains approximately 1% Cephalexin.
• compositions can be made in accordance with Example 42 which include Cephalexin in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing cephalexin is obtained as follows. Mix the following ingredients in the ⁇ imounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• Example 43 contains approximately 1% Cephalexin.
• compositions can be made in accordance with Example 43 which include Cephalexin in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing Cephalexin is obtained as follows. Mix the following ingredients in the amounts specified.
• Purified water balance Citric acid can be used to adjust the pH to a desired level.
• Example 44 contains approximately 1% Cephalexin.
• Cephalexin in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing cephalexin is obtained as follows.
• Purified water balance Citric acid can be used to adjust the pH to a desired level.
• Example 45 contains approximately 1% Cephalexin.
• Example 45 Other suitable compositions can be made in accordance with Example 45 which include
• a topical dermatological composition containing cefaclor is obtained as follows. Mix the following ingredients in the amounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• Example 46 contains approximately 2% Cefaclor.
• Example 46 Other suitable compositions can be made in accordance with Example 46 which include Cefaclor in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing cefaclor is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• Citric acid can be used to adjust the pH to a desired level.
• the composition in Example 47 contains approximately 1% Cefaclor.
• Example 47 Other suitable compositions can be made in accordance with Example 47 which include Cefaclor in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing cefuroxime is obtained as follows. Mix the following ingredients in the amounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• the composition in Example 48 contains approximately 1% Cefuroxime.
• Example 48 Other suitable compositions can be made in accordance with Example 48 which include Cefuroxime in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing cefuroxime is obtained as follows. Mix the following ingredients in the amounts specified.
• Purified water balance Citric acid can be used to adjust the pH to a desired level.
• Example 49 contains approximately 1% Cefuroxime.
• Cefuroxime in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• cefuroxime axetil is th 1-acetyloxy ethyl ester of cefuroxime. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• Citric acid can be used to adjust the pH to a desired level.
• Example 50 contains approximately 1% Cefuroxime axetil.
• Other suitable compositions can be made in accordance with Example 50 which include Cefuroxime axetil in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing cefuroxime axetil is obtained as follows. Mix the following ingredients in the amounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• Example 51 contains approximately 1% Cefuroxime axetil.
• Example 51 Other suitable compositions can be made in accordance with Example 51 which include Cefuroxime axetil in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing cefoperazone is obtained as follows. Mix the following ingredients in the amounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• the composition in Example 52 contains approximately 1% Cefoperazone.
• Example 52 Other suitable compositions can be made in accordance with Example 52 which include Cefoperazone in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing cefoperazone is obtained as follows. Mix the following ingredients in the ⁇ unounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• Example 53 contains approximately 1% Cefoperazone.
• Example 53 Other suitable compositions can be made in accordance with Example 53 which include Cefoperazone in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing ampicillin is obtained as follows. Mix the following ingredients in the amounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• Example 54 contains approximately 1% Ampicillin.
• Other suitable compositions can be made in accordance with Example 54 which include Ampicillin in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• Example 55 A topical dermatological composition containing amoxicillin is obtained as follows.
• Citric acid can be used to adjust the pH to a desired level.
• Example 55 contains approximately 1% Amoxicillin.
• Other suitable compositions can be made in accordance with Example 55 which include
• a topical dermatological composition containing ceftin is obtained as follows. Mix the following ingredients in the ⁇ unounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• Example 56 contains approximately 1% Ceftin.
• compositions can be made in accordance with Ex ⁇ unple 56 which include Ceftin in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• a topical dermatological composition containing ceftin is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• Citric acid can be used to adjust the pH to a desired level.
• the composition in Ex ⁇ unple 57 contains approximately 1% Ceftin.
• compositions can be made in accordance with Example 57 which include Ceftin in the following percentages: 0.5%, 2%, 3%, 4%, 5%, and 10%.
• topical gel compositions containing the antibiotic erythromycin and benzoyl peroxide in a gel carrier are disclosed.
• a number of topical gel compositions of the present invention can be made by simply replacing the erythromycin disclosed in the gel compositions in said patent with ampicillin, amoxicillin, or cephalosporin C, respectively, to provide topical gel compositions of the invention which contain benzoyl peroxide and the respective antibiotic of the invention.
• the gel carrier or vehicle for Examples 58- 60, prior to addition of the benzoyl peroxide and prior to addition of the respective antibiotic of the invention and, as explained below, the approximately 3 ml. of ethyl alcohol used to dissolve the respective antibiotic for addition to the gel carrier to which benzoyl peroxide has been added, is comprised of the following ingredients in the approximate amounts specified.
• Carboxy vinyl polymer (acid form) 1.00 Water, deionized or distilled 54.65
• a topical dermatological gel composition containing ampicillin antibiotic and benzoyl peroxide in a gel carrier or vehicle is obtained as follows. To a first container add the benzoyl peroxide and the gel carrier or vehicle ingredients (approximately 5 grams of benzoyl peroxide and approximately 89 grams of gel carrier or vehicle) . To a second container add powdered ampicillin (approximately 3 grams of ampicillin) . The contents of the first container and the contents of the second container are stable for long periods of time.
• a quantity of 70% ethyl alcohol e. g.
• the blended topical gel composition of the invention with contains ampicillin and benzoyl peroxide in a gel carrier or vehicle has the following components in the approximate amounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• Example 58 contains approximately 3% ampicillin.
• compositions can be made in accordance with Example 58 which include ampicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a topical dermatological gel composition containing amoxicillin antibiotic and benzoyl peroxide in a gel carrier or vehicle is obtained as follows. To a first container add the benzoyl peroxide and the gel carrier or vehicle ingredients (approximately 5 grams of benzoyl peroxide and approximately 89 grams of gel carrier or vehicle) . To a second container add powdered amoxicillin (approximately 3 grams of amoxicillin) . The contents of the first container and the contents of the second container are stable for long periods of time.
• a quantity of 70% ethyl alcohol e. g.
• the blended topical gel composition of the invention with contains amoxicillin and benzoyl peroxide in a gel carrier or vehicle has the following components in the approximate amounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• Example 59 contains approximately 3% amoxicillin.
• Other suitable compositions can be made in accordance with Example 59 which include amoxicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• Example 60 A topical dermatological gel composition containing cephalosporin C antibiotic and benzoyl peroxide in a gel carrier or vehicle is obtained as follows.
• the alcoholic solution of cephalosporin C is added to the first container, and all the ingredients are mixed to form the topical gel composition of the invention which contains both cephalosporin C and benzoyl peroxide.
• This composition of the invention is stable, under refrigeration, for approximately 3 months.
• the blended topical gel composition of the invention with contains cephalosporin C and benzoyl peroxide in a gel carrier or vehicle has the following components in the approximate amounts specified.
• Citric acid can be used to adjust the pH to a desired level.
• Example 60 contains approximately 3% cephalosporin C.
• Example 60 Other suitable compositions can be made in accordance with Example 60 which include cephalosporin C in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• Example 61
• a dermatological lotion containing amoxicillin is obtained by mixing the following ingredients in the amounts specified.
• the ingredients in Container A is blended with the ingredients in Container B.
• Citric acid can be used to adjust the pH to a desired level.
• the composition in Container A is prepared. This composition in Container A is stable for long periods of time.
• Container B can contain only amoxicillin for a long period of time. Just prior to forming the complete lotion composition, 3 grams of acetone are added to Container B to dissolve the amoxicillin. Then, the contents of Container A and Container B are combined to form the complete lotion composition of the invention.
• Example 61 contains approximately 3% amoxicillin.
• compositions can be made in accordance with Example 61 which include amoxicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a dermatological lotion containing cephalosporin C is obtained by mixing the following ingredients in the amounts specified.
• the ingredients in Container A is blended with the ingredients in Container B.
• Container B Ingredient Weight Per Cent of ingredient in overall lotion
• Acetone 3.00 cephalosporin C 3.00 Citric acid can be used to adjust the pH to a desired level.
• the composition in Container A is prepared. This composition in Container A is stable for long periods of time.
• Container B can contain only cephalosporin C for a long period of time. Just prior to forming the complete lotion composition, 3 grams of acetone are added to Container B to dissolve the cephalosporin C. Then, the contents of Container A and Container B are combined to form the complete lotion composition of the invention.
• the composition in Example 62 contains approximately 3% cephalosporin C.
• compositions can be made in accordance with Example 62 which include cephalosporin C in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a dermatological lotion is obtained by mixing the following ingredients in the ⁇ unounts specified:
• Ampicillin 2 Other suitable compositions can be made in accordance with Example 63 which include ampicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a dermatological lotion is obtained by mixing the following ingredients in the ⁇ unounts specified: Ingredient Weight Per Cent Ethoxylated cetyl-stearyl alcohol 7
• Ampicillin 2 Other suitable compositions can be made in accordance with Example 64 which include ampicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• Example 65 A lotion composition is obtained as follows. Mix the following ingredients in the amounts specified.
• compositions can be made in accordance with Ex ⁇ unple 65 which include ⁇ unpicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a lotion composition is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• Example 66 Other suit ⁇ le compositions can be made in accordance with Example 66 which include ampicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• EyaP-Ple 67 EyaP-Ple 67
• a dermatological lotion is obtained by mixing the following ingredients in the amounts specified: Ingredient Weight Per Cent
• Dioctyl sodium sulphosuccinate 0.1 Amoxicillin 2 Other suitable compositions can be made in accordance with Example 67 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a dermatological lotion is obtained by mixing the following ingredients in the amounts specified:
• Amoxicillin 2 Other suitable compositions can be made in accordance with Ex ⁇ unple 68 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a cream composition is obtained as follows. Mix the following ingredients in the amounts specified.
• compositions can be made in accordance with Ex ⁇ unple 69 which include ampicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a cream composition is obtained as follows. Mix the following ingredients in the ⁇ unounts specified. Ingredient Weight Per Cent Ethoxylated cetyl-stearyl alcohol 15
• compositions can be made in accordance with Example 70 which include ampicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a lotion composition is obtained as follows. Mix the following ingredients in the amounts specified.
• Example 72 Other suitable compositions can be made in accordance with Example 71 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• Example 72 include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a lotion composition is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• compositions can be made in accordance with Ex ⁇ unple 72 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a cream composition is obtained as follows.
• compositions can be made in accordance with Example 73 which include amoxicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a cream composition is obtained as follows. Mix the following ingredients in the amounts specified.
• compositions can be made in accordance with Example 74 which include amoxicillin in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a lotion composition is obtained as follows. Mix the following ingredients in the amounts specified.
• Cephalosporin C 2 Other suitable compositions can be made in accordance with Example 75 which include cephalosporin C in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• Example 76 A lotion composition is obtained as follows.
• Cephalosporin C 2 Other suitable compositions can be made in accordance with Example 76 which include cephalosporin C in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%. Examole 77
• a cream composition is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• compositions can be made in accordance with Example 77 which include cephalosporin C in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• a cream composition is obtained as follows. Mix the following ingredients in the amounts specified. Ingredient Weight Per Cent
• compositions can be made in accordance with Example 78 which include cephalosporin C in the following percentages: 0.5%, 1%, 2%, 4%, 5%, and 10%.
• Part A is comprised of a 3.33% aqueous solution of amoxicillin.
• Part B is an ointment base comprised of: Ingredient Weight Per Cent viscid paraffin 35 white vaseline 35 cetylstearyl alcohol 30
• a mixture is obtained as follows. Mix 60 ml. of Part A is mixed with 40 ml. of Part B to provide an oil-in-water emulsion in ointment form containing approximately 2% amoxicillin.
• compositions can be made in accordance with Ex ⁇ unple 79 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a mineral-oil-based amoxicillin ointment is obtained as follows.
• Part A is comprised of a 6.66% aqueous solution of amoxicillin.
• Part B is an ointment base comprised of: Ingredient Parts glycerin 5 isopropyl alcohol, 96% 5 mineral oil 60
• a mixture is obtained as follows. Mix 30 ml. of Part A with 70 ml. of Part B to provide a mineral-oil-based ointment containing approximately 2% amoxicillin.
• compositions can be made in accordance with Example 80 which include amoxicillin in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• Part A is comprised of a 3.33% aqueous solution of cephalosporin C.
• Part B is an ointment base comprised of: Ingredient Weight Per Cent viscid paraffin 35 white vaseline 35 cetylstearyl alcohol 30
• a mixture is obtained as follows. Mix 60 ml. of Part A is mixed with 40 ml. of Part B to provide an oil-in-water emulsion in ointment form containing approximately 2% cephalosporin C.
• compositions can be made in accordance with Example 81 which include cephalosporin C in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a mineral-oil-based cephalosporin C ointment is obtained as follows. Part A is comprised of a 6.66% aqueous solution of cephalosporin C.
• Part B is an ointment base comprised of: Ingredient Parts glycerin 5 isopropyl alcohol, 96% 5 mineral oil 60
• a mixture is obtained as follows. Mix 30 ml. of Part A with 70 ml. of Part B to provide a mineral-oil-based ointment containing approximately 2% cephalosporin C.
• compositions can be made in accordance with Example 82 which include cephalosporin C in the following percentages: 0.5%, 1%, 3%, 4%, 5%, and 10%.
• a number of patients having acne vulgaris have been successfully treated with 2% topical ampicillin, and the case histories are described as follows.
• Patient number one is a male and began treatment at the age of sixteen for acne vulgaris. Over the course of one year, he had been treated with the following agents in the order specified: first, retin-A and Benzamycin gel topically; second, oral ampicillin in conjunction with topical erythromycin solution and topical retin-A (it is noted that therapeutic doses of oral ampicillin gave the patient diarrhea) ; third, low dose oral ampicillin (250 mgm per day) in conjunction with topical retin-A and topical clindamycin solution; fourth, retin-A and clindamycin solution alone without any oral medication.
• the second patient is a female, and at the time of first treatment was 12 years old. She had acne vulgaris which was treated with the following combinations of treatments over a two year period in the order specified: first, a combination of topical retin-A and Benz ⁇ unycin gel; second, oral ampicillin in conjunction with retin-A, topical clindamycin solution, and topical benzoyl peroxide; third, topical clindamycin and topical retin-A and a 2% salicylic acid wash.
• This patient was to start taking a birth control pill (Orthonovum, 1/35) for oral contraception. Due to the possible side effects of oral antibiotic decreasing the effectiveness of the birth control pill, the inventor and the patient elected to stop the oral ampicillin. The patient was placed on topical benzoyl peroxide, topical clindamycin gel, and continued on topical retin-A. Benzamycin gel was discontinued.
• the topical clindamycin Upon treatment with the 2% ⁇ unpicillin of the invention, the topical clindamycin was discontinued. The topical retin-A and benzoyl peroxide were continued at their same doses. Approximately seven weeks later, the patient remarked that her condition had improved with the topical ampicillin. On physical examination, the patient had on her face, 0.5+ pustules on the right cheek and 0 pustules on the left cheek, 0.5+ papules, and 0.5+ comedones. The patient was approximately 50% improved clinically over the last seven weeks. Due to the success of the topical ampicillin, the patient elected to continue topical ampicillin. The other topical medications (retin-A and benzoyl peroxide) were continued as well. Photos were again taken.
• the fourth patient is a male and began treatment at age 12 for acne vulgaris. He was first treated with topical clindamycin gel and benzoyl peroxide. His acne vulgaris worsened by age 14 and required oral ampicillin 1 gram a day. topical retin-A, and Benzamycin gel. The severity of the acne worsened so much by age 15 that oral ACCUTANE was discussed. The parents did not want to continue oral antibiotics or have their son take ACCUTANE due to side effects.
• the fifth patient is male and began treatment at age 12 for acne vulgais. He had been treated with oral antibiotics including oral erythromycin, oral minocycline, topical retin-A, and benzoyl peroxide lotion. He failed this treatment regimen due to severe acne vulgaris which necessitated treatment with oral ACCUTANE for 20 weeks. Even during his course of ACCUTANE, which is reserved for severe acne unresponsive to oral antibiotics, he showed resistance and upon discontinuance of this oral agent he required oral ampicillin, and topical retin-A.
• oral antibiotics including oral erythromycin, oral minocycline, topical retin-A, and benzoyl peroxide lotion. He failed this treatment regimen due to severe acne vulgaris which necessitated treatment with oral ACCUTANE for 20 weeks. Even during his course of ACCUTANE, which is reserved for severe acne unresponsive to oral antibiotics, he showed resistance and upon discontinuance of this oral agent he required oral ampicillin, and topical retin-A.
• her acne started to clear within 2 weeks of commencing treatment with topical 2% ampicillin.
• her face revealed 1+ comedones, 0+ pustules, right cheek 0+ papules, left cheek 0.5+ papules. She was approximately 75% cleared from her previous examination seven weeks prior. Photos were again taken.
• Table I illustrates in summary form the six patients treated with the invention 2% topical ampicillin:
• the weight percent of ethyl alcohol spans 35% to 98.5%. More specifically, the weight percents of ethyl alcohol are as follows: 35.0% in Example 17; 35.0% in Example 16; 41.5% for the treated Patients; 41.0% in Example 1; 44.0% in Example 13; 48.0% in Example 54; 65% in Example 12; 71.2% in Example 3; and 98.5% in Example 12.
• the weight percent of isopropyl alcohol spans 4% to 80%. More specifically, the weight percents of isopropyl alcohol are as follows: 4.0% in Example 54; 4.3% in Example 25; 6.0% for the treated Patients; 6.0% in Exaple 13; and 80.0% in Example 39.
• the weight percent of propylene glycol spans 3% to 26.8%. More specifically, the weight percents of propylene glycol are as follows: 3.0% in Example 6; 3.0% in Example 9; 3.0% in Example 30; 10.0% in Example 54; 10.0% in Example 39; and 26.8% in Example 3.
• the weight percent of glycerin is 6.9% in Ex ⁇ unple 25. It is well known that ethyl alcohol, isopropyl alcohol, propylene glycol, and glycerin are water-miscible alcohols that can be applied topically to the skin.
• the carrier ingredients for the antibiotic can be one water- miscible solvent (ethyl alcohol) without the presence of water. More generally, the lowest weight percent for a water-miscible alcohol used in a carrier for the antibiotic is 3% as disclosed in Examples 6, 9 and 30 which disclose 3% propylene glycol. It is seen in Example 3 that the carrier ingredients for the antibiotic can be two water- miscible solents (ethyl alcohol and propylene glycol) without the presence of water.
• the carrier ingredients for the antibiotic can be two or more water-miscible solvents in the presence of water.
• the highest weight percent for two or more water-miscible solvents in the presence of water as carriers for the antibiotic is 99.5% disclosed in Example 13.
• the widest range for a water-miscible alcohol either alone, or in combination with another water-miscible alcohol or water, in weight percent is 3% to 99.5%.
• the sums of the weight percents of the water-miscible alcohols span 11.2% to 90%. More specifically, the sums of the weight percents of the water-miscible alcohols are as follows: 11.2% in Ex ⁇ unple 25; 47.5% for the treated Patients; 50.0% in Example 13; 62.0% in Example 54; and 90.0% in Example 39.
• the sums of the weight percents of the water-miscible alcohols spans 42.4% to 99.5%. More specifically, the sums of the weight percents of the water-miscible alcohols and water are as follows: 42.2% in Example 25; 73.8% in Example 30; 74.8% in Example 9; 86.6% in Example 16; 90.0% in Example 17; 97.5% for the treated Patients; 98.0% in Example 6; 98.5% in Example 54; 99.0% in Example 39; and 99.5% in Example 13.

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• 1992
  • 1992-03-03 CA CA002086259A patent/CA2086259A1/en not_active Abandoned
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