WO1999022716A1 - Topical compositions for nsai drug delivery - Google Patents

Topical compositions for nsai drug delivery Download PDF

Info

Publication number
WO1999022716A1
WO1999022716A1 PCT/US1998/023559 US9823559W WO9922716A1 WO 1999022716 A1 WO1999022716 A1 WO 1999022716A1 US 9823559 W US9823559 W US 9823559W WO 9922716 A1 WO9922716 A1 WO 9922716A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
gum
accordance
skin penetration
ketoprofen
Prior art date
Application number
PCT/US1998/023559
Other languages
French (fr)
Inventor
Servet Buyuktimkin
Nadir Buyuktimkim
James L. Yeager
Original Assignee
Nexmed Holdings, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nexmed Holdings, Inc. filed Critical Nexmed Holdings, Inc.
Priority to IL13588698A priority Critical patent/IL135886A/en
Priority to EP98956603A priority patent/EP1028710A4/en
Priority to KR1020007004899A priority patent/KR100621817B1/en
Priority to CA002309178A priority patent/CA2309178C/en
Priority to BR9813947-9A priority patent/BR9813947A/en
Priority to JP2000518650A priority patent/JP2001521887A/en
Publication of WO1999022716A1 publication Critical patent/WO1999022716A1/en
Priority to HK01105456A priority patent/HK1034898A1/en

Links

Classifications

    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/5415—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 carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

  • This invention relates to aqueous pharmaceutical compositions for transdermal administration of non- steroidal anti-inflammatory drugs to a patient.
  • Non-steroidal anti-inflammatory (hereafter NSAI) drugs have been used extensively in recent years for treatment of chronic rheumatic or arthritic conditions and for management of pain. The compounds are believed to bring relief by inhibiting biosynthesis of prostaglandins at affected joints or in other tissue areas.
  • Salicylic acid, or aspirin, and ibuprofen are well-known examples of NSAI drugs .
  • Patients taking NSAI drugs orally face an increased risk for peptic ulcers and gastrointestinal blood loss resulting in anemia. Such adverse reactions especially plague patients taking NSAI drugs over prolonged periods.
  • One solution to the gastrointestinal complications problem is to deliver the NSAI drug transdermally via a topical preparation rather than orally. Transdermal drug delivery provides other benefits as well, these include less frequent dosing, better controlled drug release, and a greater ability to target delivery to specific tissue sites.
  • topical drug formulations typically include a skin penetration enhancer.
  • Skin penetration enhancers also may be referred to as absorption enhancers, accelerants, adjuvants, solubilizers, sorption promoters, etc. Whatever the name, such agents serve to improve drug absorption across the skin.
  • Ideal penetration enhancers not only increase drug flux across the skin, but do so without irritating, sensitizing, or damaging skin. Furthermore, ideal penetration enhancers should not affect available dosage forms (e.g. cream or gel) , or the odor of the topical composition.
  • Patent No. 5,210,099 to Mody et al discloses an oil-in- water emulsion cream having crystalline form ibuprofen suspended in the oil phase with a variety of penetration enhancers.
  • U.S. Patent No. 5,093,133 to Wisniewski et al . is directed to the S-enantiomer (optical isomer) of ibuprofen in a hydroalcoholic gel, where the alcohol component is said to enhance drug absorption.
  • U.S. Patent No. 4,393,076 to Noda et al . is directed to a neutralized ketoprofen gel containing a glycol- lower alcohol mixture.
  • An aqueous pharmaceutical composition of a semi-solid consistency suitable for topical application comprises a non-steroidal anti -inflammatory (NSAI) drug, a non-basic polymeric skin penetration enhancer and a lipophilic solvent.
  • the polymeric skin penetration enhancer is present in the composition in an amount sufficient to enhance skin penetration of the NSAI drug.
  • Preferred are either a water-dispersible non-basic (acidic or neutral) polymer or a polysaccharide , or a mixture thereof.
  • the lipophilic solvent is a mixture of an aliphatic C, to C 8 alcohol and an aliphatic C 8 to C 30 ester.
  • the composition may also include a thickening agent, an emulsifying agent and/or a buffer system capable of providing a buffered pH value for the composition in the range of about 3 to physiological.
  • the NSAI drug is an ibufenac group drug and the polymeric skin penetration enhancer is a galactomannan gum.
  • FIGURE 2 is a graph of the cumulative drug penetration through shed snake skin of three additional example compositions (E through F) and the same commercial ketoprofen composition;
  • FIGURE 3 is a graph of the cumulative drug penetration through shed snake skin of five additional example compositions (H through L) and the same commercial ketoprofen composition;
  • FIGURE 4 is a graph of the cumulative drug penetration through shed snake skin of four more example compositions (M through P) and the same commercial ketoprofen composition;
  • FIGURE 5 is a graph of the cumulative drug penetration through shed snake skin of six additional example compositions (Q through V) and the same commercial ketoprofen composition
  • FIGURE 6 is a graph of the cumulative drug penetration through shed snake skin of six more example compositions (W through BB) and the same commercial ketoprofen composition;
  • FIGURE 7 is a graph of the cumulative drug penetration through shed snake skin of two additional example compositions (CC through DD) and the same commercial ketoprofen composition;
  • FIGURE 8 is a graph of cumulative drug penetration through shed snake skin of selected ketoprofen compositions prepared according to the present invention and two known ketoprofen compositions;
  • FIGURE 9 is a graph of cumulative drug penetration through shed snake skin of three topical ibuprofen compositions prepared according to the present invention and a commercial ibuprofen composition;
  • FIGURE 10 is a graph of cumulative drug penetration through human skin of a commercial ketoprofen composition and a ketoprofen composition prepared according to the present invention.
  • the pharmaceutical composition of the present invention comprises a NSAI drug, a non-basic (i.e. acid or neutral) polymeric skin penetration enhancer, and a co- acting lipophilic solvent. As prepared, this composition forms a semisolid suitable for topical application. Acid buffer systems and stabilizers may be added as necessary.
  • the composition of the present invention exhibits relatively high NSAI drug penetration and bioavailability without requiring a wasteful overloading drug concentration.
  • the composition further exhibits reduced skin irritation, sensitivity and damage.
  • the invented composition includes one or more NSAI drugs. Although most are organic acids, the NSAI group embraces a wide range of chemical structures. One common approach divides the NSAI drugs as follows:
  • salicylic acid derivatives which includes aspirin
  • propionic acids which includes ibuprofen, ketoprofen, oxaprozin, pirprofen, indobufen, tiaprofenic acid;
  • indole and indene acetic acids which includes indomethacin, sulindac, etodolac, carprofen;
  • heteroaryl acetic acids which includes diclofenac, tolmetin, ketorolac;
  • anthranilic acids which includes mefenanamic acid, etofenamat
  • enolic acids which includes piroxicam, meloxicam, tenoxicam
  • the ibufenac group includes, inter alia, both the salicylic acid derivatives and propionic acids group.
  • Ibufenac group drugs are preferred for this invention.
  • ibufenac group drugs include cliprofen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, fenbufen, alcofenac, amfenac sodium, fenclofenac, naproxen, naproxol, and diflunisal .
  • ibufenac group drugs ketoprofen is most preferred.
  • ketoprofen
  • piroxicam Preferred among the enolic acids group is piroxicam:
  • the quantity of NSAI drug in the pharmaceutical compositions of the present invention varies according to the desired dose, the solubility of the NSAI drug, and the dosage form (e.g., suppository or topical gel) .
  • the composition preferably contains between about 0.1 percent to about 10 percent NSAI drug by weight and most preferably from 0.5 percent to 10 percent based on the total weight of the composition.
  • the term skin penetration enhancer means a substance that promotes drug diffusion through the skin.
  • the polymeric skin penetration enhancer is non-basic, i.e. acid or neutral, and present in an amount sufficient to enhance the penetration of the selected NSAI drug or drug combination. The specific amount varies according to the type of enhancer, the type of NSAI drug, and the desired release rate.
  • the polymeric skin penetration enhancer preferably is a water-dispersible acid polymer or a polysaccharide gum, or a mixture of both.
  • An illustrative water-soluble acid polymer is a polyacrylic acid polymer.
  • One type of polyacrylic acid polymer formulation suitable for use in practicing this invention is known generically as "carbomer.”
  • Carbomer is polyacrylic acid polymers lightly cross-linked with polyalkenyl polyether . It is commercially available from the B. F. Goodrich Company (Akron, Ohio) under the designation "CARBOPOLTM .
  • a particularly preferred variety of carbomer is that designated as "CARBOPOL 940P.”
  • polyacrylic acid polymers suitable for use in practicing this invention are those commercially available under the designations "PemulenTM” (B. F. Goodrich Company) and “POLYCARBOPHILTM” (A.H. Robbins, Richmond, VA) .
  • the PemulenTM polymers are copolymers of C 10 to C 30 alkyl acrylates and one or more monomers of acrylic acid, methacrylic acid or one of their simple esters crosslinked with an allyl ether of sucrose or an allyl ether of pentaerythritol.
  • the POLYCARBOPHILTM enhancer is a polyacrylic acid cross-linked with divinyl glycol .
  • polyacrylic acid polymers serve as the penetration enhancer, they represent about 0.5 weight percent to about 5 weight percent of the pharmaceutical compositions of the present invention, and preferably about 2 weight percent to about 3 weight percent, based on the total weight of the composition.
  • the polyacrylic acid polymers preferably are maintained at an acidic or neutral pH.
  • Polysaccharide gums also may serve as penetration enhancers in the composition of the present invention.
  • Suitable representative gums are those in the xanthan gum category and the galactomannan gum category.
  • Gums, and galactomannan gums in particular are well-known materials. See for instance, Industrial Gums : Polysaccharides & Their Derivatives , Whistler R. L., BeMiller J.N. (eds.), 3rd Ed. Academic Press (1992) and Davidson, R. L., Handbook of Wa ter-Soluble Gums & Resins , McGraw-Hill, Inc., N.Y. (1980) .
  • a galactomannan gum is a carbohydrate polymer containing D-galactose and D-mannose units, or other derivatives of such a polymer. There is a relatively large number of galactomannans , which vary in composition depending on their origin.
  • the galactomannan gum is characterized by a linear structure of 3-D-mannopyranosyl units linked (1 ⁇ 4) . Single membered ⁇ -D-mannopyranosyl units, linked (1 ⁇ 6) with the main chain, are present as side branches.
  • Galactomannan gums include guar gum, which is the pulverized endosperm of the seed of either of two leguminous plants ⁇ cyamposis tetragonalobus and psoraloids) and locust bean gum, which is found in the endosperm of the seeds of the carob tree (ceratonia siliqua) .
  • Carob gum is also a galactomannan.
  • Suitable representative gums include agar gum, alginate, carrageenan gum, ghatti gum, karaya gum, kadaya gum, rhamsan gum, xanthan gum and derivatives of galactomannan polymers .
  • Xanthan gum is a high-molecular-weight natural carbohydrate produced in culture fermentation by the microorganism Xanthomonas campestris .
  • Xanthan gum contains three different monosaccharides : mannose, glucose, and glucuronic acid (as a mixed potassium, sodium, and calcium salt) .
  • Each repeating block of the polymer chain has five sugar units (two glucose, two mannose, one glucuronic acid) .
  • the polymer's main chain is made up of 3-D-glucose units linked through the 1- and 4 -positions ; thus, the chemical structure of the main chain is identical to that of cellulose.
  • alginates are salts of alginic acid.
  • Alginic acid comprises D-mannuronic acid and L- gluronic acid residues and has three kinds of polymer segments: one consisting of D-mannuronic acid units, a second of L-gluronic acid units, and the third of alternating D-mannuronic acid and L-gluronic acid residues.
  • Conventionally known as propylene glycol alginate, the propylene glycol ester of alginic acid is the preferred form alginate for the present invention.
  • composition of the present invention may also contain a mixture of various gums (or their derivatives) , or mixture of gums and acidic polymers.
  • polysaccharide gums serve as the penetration enhancers, they represent about 1 weight percent to about 5 weight percent, based on the total weight of the composition.
  • Illustrative compositions are given in the examples, below.
  • Suitable polymeric skin penetration enhancers are cellulose derivatives, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose.
  • transdermal penetration enhancers can also be added, if desired.
  • Illustrative are dimethyl sulfoxide (DMSO) and dimethyl acetamide (DMA) , 2- pyrrolidone, N,N-diethyl-m-toluamide (DEET) , l-dodecylazacycloheptane-2-one (Azone ® , a registered trademark of Nelson Research), N,N-dimethylformamide , N-methyl -2 -pyrrolidone , calcium thioglycolate and other enhancers such as dioxolanes, cyclic ketones, and their derivatives and so on.
  • DMSO dimethyl sulfoxide
  • DMA dimethyl acetamide
  • DEET N,N-diethyl-m-toluamide
  • Azone ® a registered trademark of Nelson Research
  • N,N-dimethylformamide N-methyl -2 -pyrrolidone
  • biodegradable absorption enhancers which are alkyl N,N-2- (disubstituted amino) alkanoates as reported in U.S. Pat. No. 4,980,378 and U.S. Pat. No. 5,082,866, both to Wong et al .
  • Preferred supplemental enhancers are alkyl 2-(N,N- disubstituted amino) -alkanoates , (N, N-disubstituted amino) - alkanol alkanoates, and a mixture of these.
  • lipophilic solvent refers to an agent that is lipophilic as well as hydrophilic and an NSAI drug solvent.
  • the lipophilic solvent is a mixture of one or more aliphatic C 1 to C 8 alcohols with one or more aliphatic C 8 to C 30 esters.
  • suitable alcohols are ethanol, n-propanol, isopropanol and glycerol, propylene glycol while suitable esters are ethyl acetate, butyl acetate, ethyl laurate, methyl propionate, isopropyl myristate and isopropyl palmitate .
  • a preferred pharmaceutical composition embodying the present invention contains lipophilic solvent in the range of about 10 percent to about 40 percent by weight based on the total weight of the composition. Where a mixture of aliphatic alcohol and aliphatic ester are employed, the preferred amount of alcohol is in the range of about 10 percent to about 35 percent, while that of aliphatic ester is in the range from about 5 percent to about 10 percent.
  • An optional but preferred component of the present invention is an acid buffer system.
  • Acid buffer systems serve to maintain or buffer the pH of compositions within a desired range.
  • the final pH value of the pharmaceutical composition of the present invention may vary within the physiologically tolerable range. Necessarily, the final pH value is not irritating to human skin. Without violating this constraint, the pH may be selected to improve NSAI drug solubility, optimize skin penetration rate or adjust consistency when required. Any suitable method of adjusting the pH value of the aqueous solutions may be used, for example, by a buffer system, or an organic base such as triethanol amine, isopropylamine, or the like, or an inorganic base such as sodium hydroxide (NaOH) . With these factors accounted for, the preferred pH value is about 3 to physiological. Where ketoprofen is the NSAI drug, the preferred pH range is from about 4.5 to about 5.5.
  • buffer system or “buffer” as used herein has reference to a solute agent or agents which, when in a water solution, stabilize such solution against a major change in pH (or hydrogen ion concentration or activity) when acids or bases are added thereto. Solute agent or agents which are thus responsible for a resistance to change in pH from a starting buffered pH value in the range indicated above are well known.
  • the remaining component of the composition is water.
  • the composition contains water in the range of about 60 to about 90 percent, based on the total weight of the composition.
  • the specific amount of water present is not critical, however, being adjustable to obtain the desired consistency and/or concentration of the other components.
  • Contemplated dosage forms of the semi-solid pharmaceutical composition of the present invention are creams, gels, and the like, also including but not limited to compositions suitable for use with transdermal patches and like devices.
  • Part A an aqueous solution of the polymeric skin penetration enhancer
  • this solution comprises the polymer in distilled water.
  • the desired amount of skin penetration enhancer is weighed and dispersed in water or a suitably buffered aqueous system.
  • Part B the desired amount of NSAI drug is weighed and dissolved with the desired amount of the lipophilic solvent. Heat and rigorous agitation may be used to effect complete dissolution of the NSAI drug.
  • Mixing of Parts A and B is followed optionally by neutralization and pH, which results in gelling of the composition.
  • the optional buffer system is a phosphate buffer.
  • the resulting homogeneous gels when compared to heretofore available NSAI topical composition, exhibit the advantageous properties described above, including improved NSAI drug permeation and bioavailability without drug overloading, reduced skin damage and related inflammation, and increased flexibility in design of dosage forms.
  • These compositions can be used for prolonged treatment of arthritis and other disorders treated by NSAI drugs, while avoiding the gastrointestinal complications associated with oral dose delivery.
  • Application of NSAI drugs in a topical composition of the present invention to the skin of a patient allows a predetermined amount of the NSAI drug to be administered continuously to the patient and avoids undesirable effects present with a single or multiple administrations of larger dosages. By maintaining a sustained dosage rate, the NSAI drug level in the patient's blood can be better maintained within the optimal therapeutic range.
  • Composition A was prepared as follows. Part A was formed when two parts polymeric skin penetration enhancer (polyacrylic acid polymer, CARBOPOL 940 ® ) were dissolved in 60.5 ml of nanopure water. Part B was prepared by mixing 30 parts of ethanol, 5 parts of isopropyl myristate, and 2.5 parts of ketoprofen. Parts A and B were then thoroughly mixed. TABLE 1, below, contains a list of ingredients . The resulting composition was evaluated for skin penetration using shed snake skin as a model barrier. Shed snake skin was obtained from the Animal Care Unit of the University of Kansas. With head and tail sections removed, the skin was randomly divided into test sections and then hydrated by soaking.
  • polymeric skin penetration enhancer polyacrylic acid polymer, CARBOPOL 940 ®
  • the samples were then evaluated using Franz -type Diffusion Cells (surface area 1.8 cm 2 ) .
  • skin pieces were mounted on top of a receptor cell of a vertical diffusion cell assembly in which a small magnetic bar was inserted and filled with an isotonic buffer. A seal was placed on top of the skin section followed by a donor cell. The two cells were then clamped together.
  • the vials were placed on the skin in the donor cell. To reduce the evaporation of the ingredients, the donor cell and vial were gently taped together with a water-resistant adhesive band. The cells were transferred to a stirred water bath (32°C.) . Samples were withdrawn from the cells periodically and analyzed for the concentration of NSAI drug, with changes in concentration indicating the amount penetrating.
  • ketoprofen from Composition A was compared to a commercial topical ketoprofen composition (Profenid, Rhone-Poulenc Rorer) . Tests with multiple skin samples yielded data for averaging.
  • the ketoprofen of Composition A penetrated relatively faster compared to the commercial composition.
  • the results of the penetration study are presented in TABLE 6, below, and in FIGURE 1.
  • Composition B was prepared using the ingredients listed in TABLE 1, below.
  • the polymeric skin penetration enhancer used was polyacrylic acid polymer (CARBOPOL ® 940) .
  • the lipophilic solvent used was a mixture of ethanol and ethyl laurate .
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE
  • composition B penetrated relatively faster compared to the commercial composition.
  • Composition C was prepared using the ingredients listed in TABLE 1, below.
  • the polymeric skin penetration enhancer used was polyacrylic acid polymer (CARBOPOL ® 940) .
  • the lipophilic solvent used was a mixture of ethanol, glycerol, and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 1. Composition C penetrated relatively faster compared to the commercial composition.
  • Composition D was prepared using the ingredients listed in TABLE 1, below.
  • the polymeric skin penetration enhancer used was polyacrylic acid polymer (CARBOPOL ® 940) .
  • the lipophilic solvent used was a mixture of isopropanol and isopropyl myristate. Skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE
  • Part B ketoprofen 2.5 2.5 2.5 2.5 ethanol 30 30 15 - isopropanol - - 30 glycerol - - 15 - isopropyl 5 - 5 5 myristate ethyl laurate - 5 - -
  • Composition E was prepared using the ingredients listed in TABLE 2, below.
  • the polymeric skin penetration enhancer used was the galactomannan gum, locust bean gum.
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 2.
  • Composition F was prepared using the ingredients listed in TABLE 2, below.
  • the polymeric skin penetration enhancer used was the galactomannan gum, locust bean gum.
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 2.
  • EXAMPLE 7 Ketoprofen Composition G
  • Composition G was prepared using the ingredients listed in TABLE 2, below.
  • the polymeric skin penetration enhancer used was prehydrated locust bean gum.
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
  • Sucrose stearate was included in Composition G as a preservative.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 2. TABLE 2: Ketoprofen Locust Bean Gum Compositions
  • Part A locust bean gum 3 3 3 sucrose stearate 0.5 - 0.5 water 74 75 74
  • Composition H was prepared using the ingredients listed in TABLE 3, below.
  • the polymeric skin penetration enhancer used was the galactomannan gum, guar gum.
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3.
  • Ketoprofen Composition I Composition I was prepared using the ingredients listed in TABLE 3, below.
  • the polymeric skin penetration enhancer used was a synthetic guar gum: guar gum 2- (hydroxy-3 -trimethylammonio) -propyl ether chloride aliphatic carboxylic acid. It is commercially available from Rhone-Poulenc Rorer under the designation "Jaguar C13S.”
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3.
  • EXAMPLE 10 Ketoprofen Composition J
  • Composition J was prepared using the ingredients listed in TABLE 3, below.
  • the skin penetration enhancer used was depolymerized cationic guar gum, which is commercially available from Rhone-Poulenc Rorer under the designation "HI CARE 1000.”
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate .
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3.
  • EXAMPLE 11 Ketoprofen Composition K
  • Composition K was prepared using the ingredients listed in TABLE 3, below.
  • the polymeric skin penetration enhancer used was synthetic guar gum (Jaguar C13S) .
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3.
  • EXAMPLE 12 Ketoprofen Composition L Composition L was prepared using the ingredients listed in TABLE 3, below.
  • the polymeric skin penetration enhancer used was guar gum 2-hydroxypropyl ether. It is commercially available from Rhone-Poulenc Rorer under the designation "Jaguar HP120.”
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3.
  • EXAMPLE 13 Ketoprofen Composition M Composition M was prepared using the ingredients listed in TABLE 3, below. The polymeric skin penetration enhancer used was synthetic guar gum (Jaguar C13S) . The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 4.
  • EXAMPLE 14 Ketoprofen Composition N
  • Composition N was prepared using the ingredients listed in TABLE 3, below.
  • the polymeric skin penetration enhancer used was guar gum 2-hydroxy propyl ether (Jaguar HP120) .
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3.
  • Composition 0 was prepared using the ingredients listed in TABLE 3, below.
  • the polymeric skin penetration enhancer used was guar gum 2-hydroxy propyl ether (Jaguar HP120) .
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 4.
  • EXAMPLE 16 Ketoprofen Composition P
  • Composition P was prepared using the ingredients listed in TABLE 3, below.
  • the polymeric skin penetration enhancer used was guar gum 2-hydroxy propyl ether (Jaguar HP120) .
  • the lipophilic solvent used was a mixture of ethanol and Miglyol 840.
  • Miglyol 840 is a mixture of propylene glycol and decanoic acid, mixed diesters with octanoic acid commercially available from H ⁇ ls America (Piscataway, NJ) . Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 4.
  • Part B ketoprofen 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 ethanol 15 15 15 15 15 30 30 15 30
  • Miglyol 840 - - - - - - - - - 5 isopropyl 5 5 5 5 5 5 5 5 5 5 - myristate
  • EXAMPLE 17 Ketoprofen Compositions Q Through U Compositions Q through U were separately prepared using the ingredients listed in TABLE 4, below.
  • the polymeric skin penetration enhancer used was xanthan gum, which is commercially available from Monsanto (San Diego, CA) under the designation "KELTROL T.”
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 5.
  • EXAMPLE 18 Ketoprofen Compositions V And W
  • compositions V and W were separately prepared using the ingredients listed in TABLE 4, below.
  • the polymeric skin penetration enhancer used was xanthan gum (KELTROL T) .
  • the lipophilic solvent used was a mixture of ethanol, propylene glycol and isopropyl myristate.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURES 5 and 6.
  • EXAMPLE 19 Ketoprofen Compositions X Through Z
  • compositions X through Z were separately prepared using the ingredients listed in TABLE 4, below.
  • the polymeric skin penetration enhancer used was xanthan gum (KELTROL T) .
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 6.
  • EXAMPLE 20 Ketoprofen Composition AA
  • Composition AA was prepared using the ingredients listed in TABLE 4, below.
  • the polymeric skin penetration enhancer used was xanthan gum (KELTROL T) .
  • the lipophilic solvent used was a mixture of propylene glycol and Miglyol 810, a capric/caprylic triglyceride solution commercially available from H ⁇ ls America (Piscataway, NJ) . Ketoprofen skin penetration was measured as described in EXAMPLE 1.
  • Composition BB was prepared using the ingredients listed in TABLE 4, below.
  • the polymeric skin penetration enhancer used was xanthan gum (KELTROL T) .
  • the lipophilic solvent used was a mixture of ethanol and mixed diesters with octanoic acid and decanoic acid (Miglyol 840) .
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 6.
  • TABLE 4 Ketoprofen Xanthan Gum Compositions Ingredient (wt%) Q R S T
  • Part B ketoprofen 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 ethanol 30 30 30 30 10 isopropanol - - - - - 10 propylene glycol - - - - - 10 isopropyl 5 5 5 5 5 5 myristate
  • Part A xanthan gum 2 2 2 2 2 2 2 2 water 61 76 76 76 61 61
  • Part B ketoprofen 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 ethanol 10 15 15 15 30 30 isopropanol 10 - - - - - propylene glycol 10 - - - - - -
  • Miglyol 840 - - - - - 5 isopropyl 5 5 5 5 - - myristate
  • Ketoprofen Composition CC Composition CC was prepared using the ingredients listed in TABLE 5, below.
  • the polymeric skin penetration enhancer used was hydroxypropyl methylcellulose, which is commercially available from Dow Chemical Company (Midland, MI) under the designation "Methocel E4M Premium, NF" .
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
  • Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 7.
  • the polymeric skin penetration enhancer used was propylene glycol alginate .
  • Ketoprofen Compositions were a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 7. TABLE 5: Ketoprofen Compositions
  • Part A methylcellulose 3 -
  • FIGURES 1 through 7 show the cumulative amount of ketoprofen penetrating after 1, 2, 4, 8, 20 and 24 hours for each example composition according to the present invention as well as for the commercially available sample (Profenid) . These data demonstrate the superior ability of the present invention to delivery NSAI drugs transdermally when compared to heretofore available compositions.
  • FIGURES 1 through 7 are graphs generated from the data presented in TABLE 6. Significantly, and well represented in graphical form, compositions according to the present invention deliver effective skin penetration by ketoprofen relatively faster than the commercial composition.
  • compositions according the present invention were prepared according to the disclosure in U.S. Patent No. 5,093,133 to Wisniewski et al . (Comparative Composition 1) and U.S. Patent No. 4,393,076 to Noda et al (Comparative Composition 2) . Specifically, the following ingredients were used.
  • Comparative Composition 1 ketoprofen 2.5 wt% ethanol 44.2 wt% water 37.5 wt% methyl paraben 0.1 wt% methyl paraben
  • Comparative Composition 2 Comparative Composition 2 :
  • CARBOPOL 940 ketoprofen 2.5 wt% ethanol 30 wt% propylene glycol 30 wt% propylene carbonate 15 wt% hydroxypropylcellulose 2 wt% water 20 wt%
  • ketoprofen skin penetration of these comparative examples was measured as described in EXAMPLE 1. The results are presented in TABLE 7, below.
  • compositions according to the present invention deliver relatively more NSAI drug, relatively faster than the comparative prior art compositions.
  • EXAMPLE 25 Ibuprofen Composition EE Composition EE was prepared using the ingredients listed in TABLE 8, below.
  • the polymeric skin penetration enhancer used was polyacrylic acid polymer (CARBOPOL ® 940) .
  • the lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ibuprofen skin penetration was measured as described in EXAMPLE 1 using the same techniques applied for ketoprofen.
  • ibuprofen from Composition EE was compared to a commercial topical Ibuleve preparation (Diomed Development Ltd. (Hitchin, United Kingdon) .
  • the ibuprofen from Composition EE penetrated relatively faster compared to the commercial composition.
  • the results of the penetration study are presented in TABLE 9, below, and in FIGURE 9.
  • Ibuprofen Composition FF Composition FF was prepared using the ingredients listed in TABLE 8, below.
  • the polymeric skin penetration enhancer used was xanthan gum (KELTROL T) .
  • the lipophilic solvent used was a mixture of ethanol and iropropyl myristate. Ibuprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 9, below, and in FIGURE 9.
  • Ibuprofen Composition GG was prepared using the ingredients listed in TABLE 8, below.
  • the polymeric skin penetration enhancer used was xanthan gum (KELTROL T) .
  • the lipophilic solvent used was a mixture of ethanol, isopropanol and isopropyl myristate. The results are presented in TABLE 9, below, and in FIGURE 9.
  • the ibuprofen from Composition GG penetrated relatively faster compared to the commercial composition.
  • Part B ibuprofen 5 5 5 ethanol 30 30 15 isopropanol - - 15 isopropyl 5 5 5 myristate
  • compositions according the present invention were tested for ketoprofen penetration using human skin.
  • human breast skin samples were prepared using the heat separation technique. Skin samples were immersed in water at 60°C. for 60 seconds. The epidermal membranes were carefully teased off the underlying dermis and washed with water. After air drying, the samples were placed in a desiccator for 24 hours and then stored in a freezer. Before testing, skin pieces were removed from the freezer, held at room temperature for 4 hours, and hydrated for 30 minutes in a buffer solution. The pieces were next mounted into Franz-type Diffusion cells (surface area 1.8 cm 2 ) and evaluated as described in EXAMPLE 1. The results are tabulated below (TABLE 10) and given graphically in FIGURE 10. TABLE 10: Human Skin Testing
  • Composition Q delivers ketoprofen relatively faster and to a greater extent than the commercially available composition.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

An aqueous pharmaceutical composition of a semi-solid consistency is provided for topical application of non-steroidal anti-inflammatory (NSAI) drugs. The composition comprises one or more NSAI drugs, a non-basic polymeric skin penetration enhancer and a lipophilic solvent. The polymeric skin penetration enhancer is present in an amount sufficient to enhance skin penetration of the NSAI drug. The lipophilic solvent is a mixture of an aliphatic C2 to C8 alcohol and an aliphatic C8 to C30 ester.

Description

TOPICAL COMPOSITIONS FOR NSAI DRUG DELIVERY Technical Field of the Invention
This invention relates to aqueous pharmaceutical compositions for transdermal administration of non- steroidal anti-inflammatory drugs to a patient. Background of the Invention
Non-steroidal anti-inflammatory (hereafter NSAI) drugs have been used extensively in recent years for treatment of chronic rheumatic or arthritic conditions and for management of pain. The compounds are believed to bring relief by inhibiting biosynthesis of prostaglandins at affected joints or in other tissue areas. Salicylic acid, or aspirin, and ibuprofen are well-known examples of NSAI drugs . Patients taking NSAI drugs orally face an increased risk for peptic ulcers and gastrointestinal blood loss resulting in anemia. Such adverse reactions especially plague patients taking NSAI drugs over prolonged periods. One solution to the gastrointestinal complications problem is to deliver the NSAI drug transdermally via a topical preparation rather than orally. Transdermal drug delivery provides other benefits as well, these include less frequent dosing, better controlled drug release, and a greater ability to target delivery to specific tissue sites.
Working alone most drugs, NSAI drugs included, do not sufficiently permeate the skin to provide drug concentration levels comparable to those obtained from oral delivery. To overcome this problem, topical drug formulations typically include a skin penetration enhancer. Skin penetration enhancers also may be referred to as absorption enhancers, accelerants, adjuvants, solubilizers, sorption promoters, etc. Whatever the name, such agents serve to improve drug absorption across the skin. Ideal penetration enhancers not only increase drug flux across the skin, but do so without irritating, sensitizing, or damaging skin. Furthermore, ideal penetration enhancers should not affect available dosage forms (e.g. cream or gel) , or the odor of the topical composition. A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers , Maibach, H. I. and Smith, H. E. (eds.), CRC Press, Inc., Boca Raton, F.L. (1995), which surveys the use and the testing of various skin penetration enhancers .
Efforts at providing effective transdermal delivery of NSAI drugs are reflected in various NSAI creams and gels having such penetration enhancers. For example, U.S.
Patent No. 5,210,099 to Mody et al . discloses an oil-in- water emulsion cream having crystalline form ibuprofen suspended in the oil phase with a variety of penetration enhancers. U.S. Patent No. 5,093,133 to Wisniewski et al . is directed to the S-enantiomer (optical isomer) of ibuprofen in a hydroalcoholic gel, where the alcohol component is said to enhance drug absorption. U.S. Patent No. 4,393,076 to Noda et al . is directed to a neutralized ketoprofen gel containing a glycol- lower alcohol mixture. These and other conventional compositions suffer from one or more serious drawbacks as follows: complicated and expensive preparation steps or ingredients, wasteful drug overloading requirements, and insufficient drug penetration . Thus, there continues to be a need for improved, cost- effective compositions for transdermal drug delivery of NSAI drugs . Summary of the Invention
An aqueous pharmaceutical composition of a semi-solid consistency suitable for topical application comprises a non-steroidal anti -inflammatory (NSAI) drug, a non-basic polymeric skin penetration enhancer and a lipophilic solvent. The polymeric skin penetration enhancer is present in the composition in an amount sufficient to enhance skin penetration of the NSAI drug. Preferred are either a water-dispersible non-basic (acidic or neutral) polymer or a polysaccharide , or a mixture thereof. The lipophilic solvent is a mixture of an aliphatic C, to C8 alcohol and an aliphatic C8 to C30 ester. The composition may also include a thickening agent, an emulsifying agent and/or a buffer system capable of providing a buffered pH value for the composition in the range of about 3 to physiological. In a preferred composition, the NSAI drug is an ibufenac group drug and the polymeric skin penetration enhancer is a galactomannan gum. Brief Description of the Drawings In the drawings, FIGURE 1 is a graph of the cumulative drug penetration through shed snake skin of a commercial ketoprofen composition and four ketoprofen compositions (A through D) prepared according to the present invention;
FIGURE 2 is a graph of the cumulative drug penetration through shed snake skin of three additional example compositions (E through F) and the same commercial ketoprofen composition;
FIGURE 3 is a graph of the cumulative drug penetration through shed snake skin of five additional example compositions (H through L) and the same commercial ketoprofen composition;
FIGURE 4 is a graph of the cumulative drug penetration through shed snake skin of four more example compositions (M through P) and the same commercial ketoprofen composition;
FIGURE 5 is a graph of the cumulative drug penetration through shed snake skin of six additional example compositions (Q through V) and the same commercial ketoprofen composition; FIGURE 6 is a graph of the cumulative drug penetration through shed snake skin of six more example compositions (W through BB) and the same commercial ketoprofen composition;
FIGURE 7 is a graph of the cumulative drug penetration through shed snake skin of two additional example compositions (CC through DD) and the same commercial ketoprofen composition;
FIGURE 8 is a graph of cumulative drug penetration through shed snake skin of selected ketoprofen compositions prepared according to the present invention and two known ketoprofen compositions;
FIGURE 9 is a graph of cumulative drug penetration through shed snake skin of three topical ibuprofen compositions prepared according to the present invention and a commercial ibuprofen composition;
FIGURE 10 is a graph of cumulative drug penetration through human skin of a commercial ketoprofen composition and a ketoprofen composition prepared according to the present invention.
Detailed Description of the Invention
The pharmaceutical composition of the present invention comprises a NSAI drug, a non-basic (i.e. acid or neutral) polymeric skin penetration enhancer, and a co- acting lipophilic solvent. As prepared, this composition forms a semisolid suitable for topical application. Acid buffer systems and stabilizers may be added as necessary.
In use as a topical agent, the composition of the present invention exhibits relatively high NSAI drug penetration and bioavailability without requiring a wasteful overloading drug concentration. The composition further exhibits reduced skin irritation, sensitivity and damage.
The invented composition includes one or more NSAI drugs. Although most are organic acids, the NSAI group embraces a wide range of chemical structures. One common approach divides the NSAI drugs as follows:
(1) salicylic acid derivatives, which includes aspirin; (2) propionic acids, which includes ibuprofen, ketoprofen, oxaprozin, pirprofen, indobufen, tiaprofenic acid;
(3) para-aminophenol derivatives, which includes acetaminophen;
(4) indole and indene acetic acids, which includes indomethacin, sulindac, etodolac, carprofen; (5) heteroaryl acetic acids, which includes diclofenac, tolmetin, ketorolac;
(6) anthranilic acids (or fenamates) , which includes mefenanamic acid, etofenamat; (7) enolic acids, which includes piroxicam, meloxicam, tenoxicam; and
(8) alkanones .
The above groups are described in Chapter 27 of Goodman and
Gilman ' s The Pharmacological Basis of Therapeutics, 9th Ed., McGraw-Hill Inc., New York, N.Y. (1995). The Cutting' s Handbook of Pharmacology characterizes the ibufenac group, a grouping of NSAI drugs based on structural relationship to ibufenac:
Figure imgf000007_0001
[Cutting's Handbook of Pharmacology, 7th Ed. , Whitehouse
Station, Appleton-Century-Crotts , C.T. (1984) , pp. 615- 617.] The ibufenac group includes, inter alia, both the salicylic acid derivatives and propionic acids group.
Ibufenac group drugs are preferred for this invention.
Examples of suitable ibufenac group drugs include cliprofen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, fenbufen, alcofenac, amfenac sodium, fenclofenac, naproxen, naproxol, and diflunisal . Among ibufenac group drugs, ketoprofen is most preferred.
Specific compounds falling within the foregoing classes of NSAI drugs are well known to those skilled in the art and reference may be had to various literature references for their chemical structures, pharmacological activities, side effects, and normal oral dosage ranges.
See for example, Physician ' s Desk Reference, 51st Ed. (1997), The Merck Index, 12th Ed., Merck & Co., N.J. (1996), and Martindale The Extra Pharmacopoeia , 28th Ed.,
London, The Pharmaceutical Press (1982). Structural formulas for representative ibufenac group drugs are set forth below:
Figure imgf000008_0001
ibufenac :
ibuprofen:
Figure imgf000008_0002
alcofenac :
Figure imgf000008_0003
ketoprofen :
f lurbiprof en :
Figure imgf000008_0004
fenoprofen :
Figure imgf000009_0001
naproxen :
Figure imgf000009_0002
fenbufen :
Figure imgf000009_0003
Compounds referenced herein are intended to encompass pharmaceutically acceptable derivatives of the compound, including acceptable salts such as sodium salts .
Preferred among the enolic acids group is piroxicam:
Figure imgf000009_0004
The quantity of NSAI drug in the pharmaceutical compositions of the present invention varies according to the desired dose, the solubility of the NSAI drug, and the dosage form (e.g., suppository or topical gel) . The composition preferably contains between about 0.1 percent to about 10 percent NSAI drug by weight and most preferably from 0.5 percent to 10 percent based on the total weight of the composition.
An important component of the invention is the polymeric skin penetration enhancer. As used herein, the term skin penetration enhancer means a substance that promotes drug diffusion through the skin. The polymeric skin penetration enhancer is non-basic, i.e. acid or neutral, and present in an amount sufficient to enhance the penetration of the selected NSAI drug or drug combination. The specific amount varies according to the type of enhancer, the type of NSAI drug, and the desired release rate.
The polymeric skin penetration enhancer preferably is a water-dispersible acid polymer or a polysaccharide gum, or a mixture of both. An illustrative water-soluble acid polymer is a polyacrylic acid polymer. One type of polyacrylic acid polymer formulation suitable for use in practicing this invention is known generically as "carbomer." Carbomer is polyacrylic acid polymers lightly cross-linked with polyalkenyl polyether . It is commercially available from the B. F. Goodrich Company (Akron, Ohio) under the designation "CARBOPOL™ . " A particularly preferred variety of carbomer is that designated as "CARBOPOL 940P."
Other polyacrylic acid polymers suitable for use in practicing this invention are those commercially available under the designations "Pemulen™" (B. F. Goodrich Company) and "POLYCARBOPHIL™" (A.H. Robbins, Richmond, VA) . The Pemulen™ polymers are copolymers of C10 to C30 alkyl acrylates and one or more monomers of acrylic acid, methacrylic acid or one of their simple esters crosslinked with an allyl ether of sucrose or an allyl ether of pentaerythritol. The POLYCARBOPHIL™ enhancer is a polyacrylic acid cross-linked with divinyl glycol . Where polyacrylic acid polymers serve as the penetration enhancer, they represent about 0.5 weight percent to about 5 weight percent of the pharmaceutical compositions of the present invention, and preferably about 2 weight percent to about 3 weight percent, based on the total weight of the composition. The polyacrylic acid polymers preferably are maintained at an acidic or neutral pH.
Polysaccharide gums also may serve as penetration enhancers in the composition of the present invention. Suitable representative gums are those in the xanthan gum category and the galactomannan gum category. Gums, and galactomannan gums in particular, are well-known materials. See for instance, Industrial Gums : Polysaccharides & Their Derivatives , Whistler R. L., BeMiller J.N. (eds.), 3rd Ed. Academic Press (1992) and Davidson, R. L., Handbook of Wa ter-Soluble Gums & Resins , McGraw-Hill, Inc., N.Y. (1980) .
A galactomannan gum is a carbohydrate polymer containing D-galactose and D-mannose units, or other derivatives of such a polymer. There is a relatively large number of galactomannans , which vary in composition depending on their origin. The galactomannan gum is characterized by a linear structure of 3-D-mannopyranosyl units linked (1→4) . Single membered α-D-mannopyranosyl units, linked (1→6) with the main chain, are present as side branches. Galactomannan gums include guar gum, which is the pulverized endosperm of the seed of either of two leguminous plants { cyamposis tetragonalobus and psoraloids) and locust bean gum, which is found in the endosperm of the seeds of the carob tree (ceratonia siliqua) . Carob gum is also a galactomannan.
Other suitable representative gums include agar gum, alginate, carrageenan gum, ghatti gum, karaya gum, kadaya gum, rhamsan gum, xanthan gum and derivatives of galactomannan polymers . Xanthan gum is a high-molecular-weight natural carbohydrate produced in culture fermentation by the microorganism Xanthomonas campestris . Xanthan gum contains three different monosaccharides : mannose, glucose, and glucuronic acid (as a mixed potassium, sodium, and calcium salt) . Each repeating block of the polymer chain has five sugar units (two glucose, two mannose, one glucuronic acid) . The polymer's main chain is made up of 3-D-glucose units linked through the 1- and 4 -positions ; thus, the chemical structure of the main chain is identical to that of cellulose.
Also a polysaccharide, alginates are salts of alginic acid. Alginic acid comprises D-mannuronic acid and L- gluronic acid residues and has three kinds of polymer segments: one consisting of D-mannuronic acid units, a second of L-gluronic acid units, and the third of alternating D-mannuronic acid and L-gluronic acid residues. Conventionally known as propylene glycol alginate, the propylene glycol ester of alginic acid is the preferred form alginate for the present invention.
The composition of the present invention may also contain a mixture of various gums (or their derivatives) , or mixture of gums and acidic polymers.
Where polysaccharide gums serve as the penetration enhancers, they represent about 1 weight percent to about 5 weight percent, based on the total weight of the composition. Illustrative compositions are given in the examples, below.
Other suitable polymeric skin penetration enhancers are cellulose derivatives, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose.
Additionally, known transdermal penetration enhancers can also be added, if desired. Illustrative are dimethyl sulfoxide (DMSO) and dimethyl acetamide (DMA) , 2- pyrrolidone, N,N-diethyl-m-toluamide (DEET) , l-dodecylazacycloheptane-2-one (Azone®, a registered trademark of Nelson Research), N,N-dimethylformamide , N-methyl -2 -pyrrolidone , calcium thioglycolate and other enhancers such as dioxolanes, cyclic ketones, and their derivatives and so on. Also illustrative are a group of biodegradable absorption enhancers which are alkyl N,N-2- (disubstituted amino) alkanoates as reported in U.S. Pat. No. 4,980,378 and U.S. Pat. No. 5,082,866, both to Wong et al . Preferred supplemental enhancers are alkyl 2-(N,N- disubstituted amino) -alkanoates , (N, N-disubstituted amino) - alkanol alkanoates, and a mixture of these.
Another important component of the present invention is a lipophilic solvent. The term lipophilic solvent as used herein refers to an agent that is lipophilic as well as hydrophilic and an NSAI drug solvent. The lipophilic solvent is a mixture of one or more aliphatic C1 to C8 alcohols with one or more aliphatic C8 to C30 esters. Illustrative suitable alcohols are ethanol, n-propanol, isopropanol and glycerol, propylene glycol while suitable esters are ethyl acetate, butyl acetate, ethyl laurate, methyl propionate, isopropyl myristate and isopropyl palmitate . Preferred are mixtures of ethanol, isopropanol or propylene glycol with isopropyl myristate. The concentration of lipophilic solvent required necessarily varies according to other factors such as the solubility of the NSAI drug, the desired semi-solid consistency, and desired skin penetration promoting effects . A preferred pharmaceutical composition embodying the present invention contains lipophilic solvent in the range of about 10 percent to about 40 percent by weight based on the total weight of the composition. Where a mixture of aliphatic alcohol and aliphatic ester are employed, the preferred amount of alcohol is in the range of about 10 percent to about 35 percent, while that of aliphatic ester is in the range from about 5 percent to about 10 percent.
An optional but preferred component of the present invention is an acid buffer system. Acid buffer systems serve to maintain or buffer the pH of compositions within a desired range.
The final pH value of the pharmaceutical composition of the present invention may vary within the physiologically tolerable range. Necessarily, the final pH value is not irritating to human skin. Without violating this constraint, the pH may be selected to improve NSAI drug solubility, optimize skin penetration rate or adjust consistency when required. Any suitable method of adjusting the pH value of the aqueous solutions may be used, for example, by a buffer system, or an organic base such as triethanol amine, isopropylamine, or the like, or an inorganic base such as sodium hydroxide (NaOH) . With these factors accounted for, the preferred pH value is about 3 to physiological. Where ketoprofen is the NSAI drug, the preferred pH range is from about 4.5 to about 5.5.
The term "buffer system" or "buffer" as used herein has reference to a solute agent or agents which, when in a water solution, stabilize such solution against a major change in pH (or hydrogen ion concentration or activity) when acids or bases are added thereto. Solute agent or agents which are thus responsible for a resistance to change in pH from a starting buffered pH value in the range indicated above are well known.
The remaining component of the composition is water. The composition contains water in the range of about 60 to about 90 percent, based on the total weight of the composition. The specific amount of water present is not critical, however, being adjustable to obtain the desired consistency and/or concentration of the other components.
Contemplated dosage forms of the semi-solid pharmaceutical composition of the present invention are creams, gels, and the like, also including but not limited to compositions suitable for use with transdermal patches and like devices.
The ingredients listed above may be combined in any order and manner that produces a composition comprising an NSAI drug dissolved in, and evenly dispersed, throughout a one-phase aqueous semi-solid. One available approach to preparing such compositions involves preparation of an aqueous solution of the polymeric skin penetration enhancer, which will be called "Part A." Advantageously, this solution comprises the polymer in distilled water. To form Part A, the desired amount of skin penetration enhancer is weighed and dispersed in water or a suitably buffered aqueous system. For part B, the desired amount of NSAI drug is weighed and dissolved with the desired amount of the lipophilic solvent. Heat and rigorous agitation may be used to effect complete dissolution of the NSAI drug. Mixing of Parts A and B is followed optionally by neutralization and pH, which results in gelling of the composition. The optional buffer system is a phosphate buffer.
The resulting homogeneous gels, when compared to heretofore available NSAI topical composition, exhibit the advantageous properties described above, including improved NSAI drug permeation and bioavailability without drug overloading, reduced skin damage and related inflammation, and increased flexibility in design of dosage forms. These compositions can be used for prolonged treatment of arthritis and other disorders treated by NSAI drugs, while avoiding the gastrointestinal complications associated with oral dose delivery. Application of NSAI drugs in a topical composition of the present invention to the skin of a patient allows a predetermined amount of the NSAI drug to be administered continuously to the patient and avoids undesirable effects present with a single or multiple administrations of larger dosages. By maintaining a sustained dosage rate, the NSAI drug level in the patient's blood can be better maintained within the optimal therapeutic range.
The practice of the present invention is demonstrated in the following examples. These examples are meant to illustrate the invention rather than to limit its scope. Variations in the treating compositions which do not adversely affect the effectiveness of the NSAI drug will be evident to one skilled in the art, and are within the scope of this invention. For example, additional ingredients such as coloring agents, and the like may be included in the compositions as long as the resulting composition retains desirable properties, as described above. Unless otherwise indicated, each composition is prepared by conventionally admixing the respective indicated components together. Also, unless otherwise indicated, each composition is prepared using a buffer (buffer system) which in use provides a pH value in the range of about 3 to physiological . EXAMPLE 1: Ketoprofen Composition A
Composition A was prepared as follows. Part A was formed when two parts polymeric skin penetration enhancer (polyacrylic acid polymer, CARBOPOL 940®) were dissolved in 60.5 ml of nanopure water. Part B was prepared by mixing 30 parts of ethanol, 5 parts of isopropyl myristate, and 2.5 parts of ketoprofen. Parts A and B were then thoroughly mixed. TABLE 1, below, contains a list of ingredients . The resulting composition was evaluated for skin penetration using shed snake skin as a model barrier. Shed snake skin was obtained from the Animal Care Unit of the University of Kansas. With head and tail sections removed, the skin was randomly divided into test sections and then hydrated by soaking.
The samples were then evaluated using Franz -type Diffusion Cells (surface area 1.8 cm2) . Specifically, skin pieces were mounted on top of a receptor cell of a vertical diffusion cell assembly in which a small magnetic bar was inserted and filled with an isotonic buffer. A seal was placed on top of the skin section followed by a donor cell. The two cells were then clamped together. Known amounts of the formulations were applied on the bottom of a small capped vial (weight =5 grams) which fits exactly to the donor cell to ensure uniform distribution. The vials were placed on the skin in the donor cell. To reduce the evaporation of the ingredients, the donor cell and vial were gently taped together with a water-resistant adhesive band. The cells were transferred to a stirred water bath (32°C.) . Samples were withdrawn from the cells periodically and analyzed for the concentration of NSAI drug, with changes in concentration indicating the amount penetrating.
For a discussion of the use of shed snake skin in the evaluation of drug penetration, see U.S. Patent No. 4,771,004 to Higuchi , which is incorporated here by reference to the extent that it is not inconsistent .
The penetration of ketoprofen from Composition A was compared to a commercial topical ketoprofen composition (Profenid, Rhone-Poulenc Rorer) . Tests with multiple skin samples yielded data for averaging.
The ketoprofen of Composition A penetrated relatively faster compared to the commercial composition. The results of the penetration study are presented in TABLE 6, below, and in FIGURE 1.
EXAMPLE 2 : Ketoprofen Composition B
Composition B was prepared using the ingredients listed in TABLE 1, below. The polymeric skin penetration enhancer used was polyacrylic acid polymer (CARBOPOL® 940) .
The lipophilic solvent used was a mixture of ethanol and ethyl laurate . Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE
6, below, and in FIGURE 1. Composition B penetrated relatively faster compared to the commercial composition.
EXAMPLE 3: Ketoprofen Composition C
Composition C was prepared using the ingredients listed in TABLE 1, below. The polymeric skin penetration enhancer used was polyacrylic acid polymer (CARBOPOL® 940) .
The lipophilic solvent used was a mixture of ethanol, glycerol, and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 1. Composition C penetrated relatively faster compared to the commercial composition.
EXAMPLE 4 : Ketoprofen Composition D
Composition D was prepared using the ingredients listed in TABLE 1, below. The polymeric skin penetration enhancer used was polyacrylic acid polymer (CARBOPOL® 940) .
The lipophilic solvent used was a mixture of isopropanol and isopropyl myristate. Skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE
6, below, and in FIGURE 1. TABLE 1 : Ketoprofen Polyacrylic Acid Compositions Ingredient (wt%) A B C
Part A: CARBOPOL 940® 2 2 2 2 water 61 61 61 61
Part B: ketoprofen 2.5 2.5 2.5 2.5 ethanol 30 30 15 - isopropanol - - 30 glycerol - - 15 - isopropyl 5 - 5 5 myristate ethyl laurate - 5 - -
EXAMPLE 5: Ketoprofen Composition E
Composition E was prepared using the ingredients listed in TABLE 2, below. The polymeric skin penetration enhancer used was the galactomannan gum, locust bean gum. The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 2. EXAMPLE 6: Ketoprofen Composition F
Composition F was prepared using the ingredients listed in TABLE 2, below. The polymeric skin penetration enhancer used was the galactomannan gum, locust bean gum. The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 2. EXAMPLE 7 : Ketoprofen Composition G
Composition G was prepared using the ingredients listed in TABLE 2, below. The polymeric skin penetration enhancer used was prehydrated locust bean gum. The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Sucrose stearate was included in Composition G as a preservative. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 2. TABLE 2: Ketoprofen Locust Bean Gum Compositions
Ingredient (wt%) E F G
Part A: locust bean gum 3 3 3 sucrose stearate 0.5 - 0.5 water 74 75 74
Part B: ketoprofen 2.5 2.5 2.5 ethanol 15 15 15 isopropyl 5 5 5 myristate
EXAMPLE 8: Ketoprofen Composition H
Composition H was prepared using the ingredients listed in TABLE 3, below. The polymeric skin penetration enhancer used was the galactomannan gum, guar gum. The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3.
EXAMPLE 9: Ketoprofen Composition I Composition I was prepared using the ingredients listed in TABLE 3, below. The polymeric skin penetration enhancer used was a synthetic guar gum: guar gum 2- (hydroxy-3 -trimethylammonio) -propyl ether chloride aliphatic carboxylic acid. It is commercially available from Rhone-Poulenc Rorer under the designation "Jaguar C13S." The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3. EXAMPLE 10: Ketoprofen Composition J
Composition J was prepared using the ingredients listed in TABLE 3, below. The skin penetration enhancer used was depolymerized cationic guar gum, which is commercially available from Rhone-Poulenc Rorer under the designation "HI CARE 1000." The lipophilic solvent used was a mixture of ethanol and isopropyl myristate . Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3. EXAMPLE 11 : Ketoprofen Composition K
Composition K was prepared using the ingredients listed in TABLE 3, below. The polymeric skin penetration enhancer used was synthetic guar gum (Jaguar C13S) . The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3. EXAMPLE 12 : Ketoprofen Composition L Composition L was prepared using the ingredients listed in TABLE 3, below. The polymeric skin penetration enhancer used was guar gum 2-hydroxypropyl ether. It is commercially available from Rhone-Poulenc Rorer under the designation "Jaguar HP120." The lipophilic solvent used was a mixture of ethanol and isopropyl myristate.
Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3. EXAMPLE 13 : Ketoprofen Composition M Composition M was prepared using the ingredients listed in TABLE 3, below. The polymeric skin penetration enhancer used was synthetic guar gum (Jaguar C13S) . The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 4. EXAMPLE 14: Ketoprofen Composition N
Composition N was prepared using the ingredients listed in TABLE 3, below. The polymeric skin penetration enhancer used was guar gum 2-hydroxy propyl ether (Jaguar HP120) . The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 3. EXAMPLE 15: Ketoprofen Composition O
Composition 0 was prepared using the ingredients listed in TABLE 3, below. The polymeric skin penetration enhancer used was guar gum 2-hydroxy propyl ether (Jaguar HP120) . The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 4. EXAMPLE 16 : Ketoprofen Composition P Composition P was prepared using the ingredients listed in TABLE 3, below. The polymeric skin penetration enhancer used was guar gum 2-hydroxy propyl ether (Jaguar HP120) . The lipophilic solvent used was a mixture of ethanol and Miglyol 840. Miglyol 840 is a mixture of propylene glycol and decanoic acid, mixed diesters with octanoic acid commercially available from Hϋls America (Piscataway, NJ) . Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 4.
TABLE 3: Ketoprofen Guar Gum Compositions Ingredient (wt%) H I J K L
Part A: guar gum 3 - - - - - - 2 2
Jaguar C13S - 2 - - - 2 - - -
Jaguar HP120 - - - 2 2 2 - -
HI CARE 1000 - - 2 - - - - - - water 74 76 76 76 76 61 61 76 61 sucrose stearate 0.5 - - - - - - - -
Part B: ketoprofen 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 ethanol 15 15 15 15 15 30 30 15 30
Miglyol 840 - - - - - - - - 5 isopropyl 5 5 5 5 5 5 5 5 - myristate
EXAMPLE 17 : Ketoprofen Compositions Q Through U Compositions Q through U were separately prepared using the ingredients listed in TABLE 4, below. The polymeric skin penetration enhancer used was xanthan gum, which is commercially available from Monsanto (San Diego, CA) under the designation "KELTROL T." The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 5. EXAMPLE 18: Ketoprofen Compositions V And W
Compositions V and W were separately prepared using the ingredients listed in TABLE 4, below. The polymeric skin penetration enhancer used was xanthan gum (KELTROL T) . The lipophilic solvent used was a mixture of ethanol, propylene glycol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURES 5 and 6. EXAMPLE 19: Ketoprofen Compositions X Through Z
Compositions X through Z were separately prepared using the ingredients listed in TABLE 4, below. The polymeric skin penetration enhancer used was xanthan gum (KELTROL T) . The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 6. EXAMPLE 20: Ketoprofen Composition AA
Composition AA was prepared using the ingredients listed in TABLE 4, below. The polymeric skin penetration enhancer used was xanthan gum (KELTROL T) . The lipophilic solvent used was a mixture of propylene glycol and Miglyol 810, a capric/caprylic triglyceride solution commercially available from Hϋls America (Piscataway, NJ) . Ketoprofen skin penetration was measured as described in EXAMPLE 1.
The results are presented in TABLE 6, below, and in FIGURE
6.
EXAMPLE 21: Ketoprofen Composition BB
Composition BB was prepared using the ingredients listed in TABLE 4, below. The polymeric skin penetration enhancer used was xanthan gum (KELTROL T) . The lipophilic solvent used was a mixture of ethanol and mixed diesters with octanoic acid and decanoic acid (Miglyol 840) . Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 6. TABLE 4: Ketoprofen Xanthan Gum Compositions Ingredient (wt%) Q R S T
Part A: xanthan gum 2 2 2 2 2 2 water 61 61 61 61 61 61
Part B: ketoprofen 2.5 2.5 2.5 2.5 2.5 2.5 ethanol 30 30 30 30 30 10 isopropanol - - - - - 10 propylene glycol - - - - - 10 isopropyl 5 5 5 5 5 5 myristate
TABLE 4 (continued): Ketoprofen Xanthan Gum Compositions
Ingredient (wt%) W X Y Z AA BB
Part A: xanthan gum 2 2 2 2 2 2 water 61 76 76 76 61 61
Part B: ketoprofen 2.5 2.5 2.5 2.5 2.5 2.5 ethanol 10 15 15 15 30 30 isopropanol 10 - - - - - propylene glycol 10 - - - - -
Miglyol 810 - - - - 5 -
Miglyol 840 - - - - - 5 isopropyl 5 5 5 5 - - myristate
EXAMPLE 22: Ketoprofen Composition CC Composition CC was prepared using the ingredients listed in TABLE 5, below. The polymeric skin penetration enhancer used was hydroxypropyl methylcellulose, which is commercially available from Dow Chemical Company (Midland, MI) under the designation "Methocel E4M Premium, NF" . The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 7. EXAMPLE 23: Ketoprofen Composition DD Composition CC was prepared using the ingredients listed in TABLE 5, below. The polymeric skin penetration enhancer used was propylene glycol alginate . The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ketoprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 6, below, and in FIGURE 7. TABLE 5: Ketoprofen Compositions
Ingredient (wt%) CC DD
Part A: methylcellulose 3 -
PG alginate - 3 water 60 76
Part B: ketoprofen 2.5 2.5 ethanol 30 15 isopropyl 5 5 myristate
EXAMPLE 24: Comparison of Penetration Profiles
The cumulative amount of ketoprofen penetration were determined as described in Example 1. The results are presented in TABLE 6, below, and in FIGURES 1 through 7. TABLE 6 shows the cumulative amount of ketoprofen penetrating after 1, 2, 4, 8, 20 and 24 hours for each example composition according to the present invention as well as for the commercially available sample (Profenid) . These data demonstrate the superior ability of the present invention to delivery NSAI drugs transdermally when compared to heretofore available compositions. FIGURES 1 through 7 are graphs generated from the data presented in TABLE 6. Significantly, and well represented in graphical form, compositions according to the present invention deliver effective skin penetration by ketoprofen relatively faster than the commercial composition.
TABLE 6: Cumulative Ketoprofen Penetration (μg/cm2) Hour Commercial A B C D E F G
1 0 145 80 59 81 113 85 48
2 0 392 207 142 200 334 246 141
4 0 650 417 312 487 520 402 351
8 2.1 1432 698 631 1021 976 802 696
18 - 2222 1735 1163 1785 - - -
20 7.8 - - - - 1947 1755 1321
24 13.1 2410 2019 1405 1979 2229 2048 1515 TABLE 6 (continued): Cumulative Ketoprofen Penetration (μg/cm2) Hour H I J K L M N O P
1 115 74 63 14 21 87 121 57 51 34
2 293 171 161 55 81 245 347 160 233 112
4 487 370 352 153 223 535 745 347 450 302
8 903 761 705 372 511 1257 1532 768 867 800'
20 1781 1666 1465 976 1208 2458 2568 1531 2287 1434
24 2024 1865 1635 1167 1403 2677 2738 1738 2501 1764
'Measured at 10 Hours for Composition Q.
TABLE 6 (continued): Cumulative Ketoprofen Penetration (μglcm2) Hour R S T U V W X Y Z AA
1 160 23 59 96 125 64 31 66 9 3
2 362 97 186 220 299 178 122 160 41 19
4 798 306 473 498 725 460 248 358 134 71
8 1463 785 1159 1130 1417 1020 556 718 343 197
20 2386 1840 2362 2400 2552 2250 1290 1516 896 522
24 2569 2103 2677 2660 2872 2595 1491 1749 1052 596 TABLE 6 (continued): Cumulative Ketoprofen Penetration (/ g/cm2)
Hour BB CC DD
1 14 136 60
2 49 263 161
4 128 536 327
8 287 986 575
20 602 1674 1290
24 663 1793 1495
To further asses the effectiveness of compositions according the present invention, comparative example compositions were prepared according to the disclosure in U.S. Patent No. 5,093,133 to Wisniewski et al . (Comparative Composition 1) and U.S. Patent No. 4,393,076 to Noda et al (Comparative Composition 2) . Specifically, the following ingredients were used.
Comparative Composition 1: ketoprofen 2.5 wt% ethanol 44.2 wt% water 37.5 wt% methyl paraben 0.1 wt% methyl paraben
0.1 wt% hydroxypropylcellulose 2.5 wt% triethanolamine 0.25 wt%
Comparative Composition 2 :
CARBOPOL 940s ketoprofen 2.5 wt% ethanol 30 wt% propylene glycol 30 wt% propylene carbonate 15 wt% hydroxypropylcellulose 2 wt% water 20 wt%
The ketoprofen skin penetration of these comparative examples was measured as described in EXAMPLE 1. The results are presented in TABLE 7, below.
TABLE 7: Comparative Examples Cumulative Ketoprofen Penetration (//g/cm2) Comparative Comparative
Hour Composition 1 Composition 2
1 0 0
2 0 0
4 4 0.4
8 15 5.5
20 73 36
24 103 64
The data of TABLE 7 are compared graphically to selected compositions in FIGURE 8. The penetration data demonstrate that compositions according to the present invention deliver relatively more NSAI drug, relatively faster than the comparative prior art compositions. EXAMPLE 25: Ibuprofen Composition EE Composition EE was prepared using the ingredients listed in TABLE 8, below. The polymeric skin penetration enhancer used was polyacrylic acid polymer (CARBOPOL® 940) . The lipophilic solvent used was a mixture of ethanol and isopropyl myristate. Ibuprofen skin penetration was measured as described in EXAMPLE 1 using the same techniques applied for ketoprofen.
The penetration of ibuprofen from Composition EE was compared to a commercial topical Ibuleve preparation (Diomed Development Ltd. (Hitchin, United Kingdon) . The ibuprofen from Composition EE penetrated relatively faster compared to the commercial composition. The results of the penetration study are presented in TABLE 9, below, and in FIGURE 9.
EXAMPLE 26: Ibuprofen Composition FF Composition FF was prepared using the ingredients listed in TABLE 8, below. The polymeric skin penetration enhancer used was xanthan gum (KELTROL T) . The lipophilic solvent used was a mixture of ethanol and iropropyl myristate. Ibuprofen skin penetration was measured as described in EXAMPLE 1. The results are presented in TABLE 9, below, and in FIGURE 9.
The ibuprofen from Composition FF penetrated relatively faster compared to the commercial composition. EXAMPLE 27 : Ibuprofen Composition GG Composition GG was prepared using the ingredients listed in TABLE 8, below. The polymeric skin penetration enhancer used was xanthan gum (KELTROL T) . The lipophilic solvent used was a mixture of ethanol, isopropanol and isopropyl myristate. The results are presented in TABLE 9, below, and in FIGURE 9.
The ibuprofen from Composition GG penetrated relatively faster compared to the commercial composition.
TABLE 8: Ibuprofen Compositions Ingredient (wt%) EE FF GG
Part A: CARBOPOL 940® 2 - - xanthan gum - 2 2 water 63 63 63
Part B: ibuprofen 5 5 5 ethanol 30 30 15 isopropanol - - 15 isopropyl 5 5 5 myristate
TABLE 9: Cumulative Ibuprofen Penetration (//g/cm2) Hour Commercial EE FF GG
1 14 327 92 114
2 32 620 250 255
4 66 1039 536 532
8 135 1561 1039 994
20 334 2383 2105 2015
24 397 2657 2426 2352 EXAMPLE 28: Comparison Using Human Skin
To further asses the effectiveness of compositions according the present invention the commercial ketoprofen topical composition (Profenid) and Composition Q were tested for ketoprofen penetration using human skin.
Specifically, human breast skin samples were prepared using the heat separation technique. Skin samples were immersed in water at 60°C. for 60 seconds. The epidermal membranes were carefully teased off the underlying dermis and washed with water. After air drying, the samples were placed in a desiccator for 24 hours and then stored in a freezer. Before testing, skin pieces were removed from the freezer, held at room temperature for 4 hours, and hydrated for 30 minutes in a buffer solution. The pieces were next mounted into Franz-type Diffusion cells (surface area 1.8 cm2) and evaluated as described in EXAMPLE 1. The results are tabulated below (TABLE 10) and given graphically in FIGURE 10. TABLE 10: Human Skin Testing
Cumulative Ketoprofen Penetration (μg/cm2) Hour Composition Q Commercial
1 34 0
2 112 0
4 302 0
8 800 2
20 1434 8
24 1764 13 Confirming the results of the snake skin tests,
Composition Q delivers ketoprofen relatively faster and to a greater extent than the commercially available composition.
The foregoing is intended to be illustrative of the present invention, but not limiting. Numerous variations and modifications may be effected without departing from the true spirit and scope of the invention.

Claims

We Claim : .
1. An aqueous pharmaceutical composition, suitable for topical application, having a semi-solid consistency, and comprising: a non-steroidal anti-inflammatory drug; a non-basic polymeric skin penetration enhancer present in an amount sufficient to enhance skin penetration of said anti-inflammatory drug, said polymeric skin penetration enhancer being a member of the group consisting of a water-dispersible acid polymer, a polysaccharide gum, and a mixture thereof ; and a lipophilic solvent which is a mixture of an aliphatic C2 to C8 alcohol and an aliphatic C8 to C30 ester.
2. The composition in accordance with claim 1 wherein said anti-inflammatory drug is an ibufenac group drug .
3. The composition in accordance with claim 1 wherein said anti-inflammatory drug is an arylpropionic acid derivative.
4. The composition in accordance with claim 1 wherein said non-steroidal anti-inflammatory drug is a member of the grouping consisting of cliprofen, fenoprofen, fluprofen, ibuprofen, ketoprofen, fenbufen, alcofenac, amfenac sodium, fenclofenac, ibufenac, naproxen, naproxol , and diflunisal.
5. The composition in accordance with claim 1 wherein said anti-inflammatory drug is ketoprofen.
6. The composition in accordance with claim 1 wherein said anti-inflammatory drug is ibuprofen.
7. The composition in accordance with claim 1 wherein said anti-inflammatory drug is piroxicam.
8. The composition in accordance with claim 1 wherein said polymeric skin penetration enhancer is polyacrylic acid.
9. The composition in accordance with claim 1 wherein said polymeric skin penetration enhancer is a carbomer .
10. .The composition in accordance with claim 1 wherein said polymeric skin penetration enhancer is a galactomannan gum.
11. The composition in accordance with claim 10 wherein said galactomannan gum is guar gum.
12. The composition in accordance with claim 10 wherein said galactomannan gum is locust bean gum.
13. The composition in accordance with claim 1 wherein said polymeric skin penetration enhancer is a polysaccharide gum selected from the group consisting of agar gum, alginate, carob gum, carrageen gum, ghatti gum, guar gum, karaya gum, kadaya gum, locust bean gum, rhamsan gum, xanthan gum, and a mixture thereof.
1 . The composition in accordance with claim 1 wherein said polymeric skin penetration enhancer is a cellulose derivative.
15. The composition in accordance with claim 15 wherein said cellulose derivative is selected from the group consisting of ethyl cellulose, methyl cellulose, hyrdoxypropyl cellulose, and mixtures thereof.
16. The composition in accordance with claim 1 wherein said aliphatic C2 to C8 alcohol is selected from the group consisting of ethanol, n-propanol, isopropanol, propylene glycol, glycerol, and a mixture thereof.
17. The composition in accordance with claim 1 wherein said aliphatic C2 to C30 ester is selected from the group consisting of ethyl acetate, butyl acetate, ethyl laurate, methyl propionate, ethyl propionate, isopropyl myristate, isopropyl palmitate, and a mixture thereof.
18. The composition in accordance with claim 1 further including a buffer system capable of providing a buffered pH value for said composition in the range of about 3 to about 7.4.
PCT/US1998/023559 1997-11-05 1998-11-05 Topical compositions for nsai drug delivery WO1999022716A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
IL13588698A IL135886A (en) 1997-11-05 1998-11-05 Topical composition for nsai drug delivery
EP98956603A EP1028710A4 (en) 1997-11-05 1998-11-05 Topical compositions for nsai drug delivery
KR1020007004899A KR100621817B1 (en) 1997-11-05 1998-11-05 An aqueous pharmaceutical composition comprising NSAI drug, suitable for topical application
CA002309178A CA2309178C (en) 1997-11-05 1998-11-05 Topical compositions for nsai drug delivery
BR9813947-9A BR9813947A (en) 1997-11-05 1998-11-05 Topical compositions for drug distribution nasi
JP2000518650A JP2001521887A (en) 1997-11-05 1998-11-05 Topical composition for NSAI drug delivery
HK01105456A HK1034898A1 (en) 1997-11-05 2001-08-06 Topical compositions for nsai drug delivery.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/965,001 US6083996A (en) 1997-11-05 1997-11-05 Topical compositions for NSAI drug delivery
US08/965,001 1997-11-05

Publications (1)

Publication Number Publication Date
WO1999022716A1 true WO1999022716A1 (en) 1999-05-14

Family

ID=25509303

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/023559 WO1999022716A1 (en) 1997-11-05 1998-11-05 Topical compositions for nsai drug delivery

Country Status (12)

Country Link
US (1) US6083996A (en)
EP (1) EP1028710A4 (en)
JP (1) JP2001521887A (en)
KR (1) KR100621817B1 (en)
CN (1) CN1198586C (en)
BR (1) BR9813947A (en)
CA (1) CA2309178C (en)
HK (1) HK1034898A1 (en)
IL (1) IL135886A (en)
TR (1) TR200002159T2 (en)
TW (1) TW522021B (en)
WO (1) WO1999022716A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001002015A1 (en) * 1999-07-01 2001-01-11 The University Of Georgia Research Foundation, Inc. Composition and method for enhanced transdermal absorption of nonsteroidal anti-inflammatory drugs
EP1095659A1 (en) * 1999-10-26 2001-05-02 Deutsche Homöopathie-Union Oil-in-water emulsions stabilised by cellulose ethers as carriers for homeopathic and plant drugs
EP1304992A1 (en) * 2000-08-03 2003-05-02 Dow Pharmaceutical Sciences Topical gel delivery system
JP2003532668A (en) * 2000-05-12 2003-11-05 サノフィ−サンテラボ Pharmaceutical composition for transdermal administration of anti-inflammatory agent
WO2004010988A1 (en) * 2002-07-31 2004-02-05 Connetics Australlia Pty Ltd Percutaneous and perungual delivery system
WO2009012908A2 (en) * 2007-07-26 2009-01-29 Bayer Animal Health Gmbh Medicament for transdermal use on animals
GB2476155A (en) * 2009-12-11 2011-06-15 Reckitt Benckiser Healthcare Int Ltd Topical NSAID formulations
EP3512498A4 (en) * 2016-09-16 2020-06-10 Achelios Therapeutics, Inc. Topical anti-inflammatory compositions

Families Citing this family (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020048596A1 (en) * 1994-12-30 2002-04-25 Gregor Cevc Preparation for the transport of an active substance across barriers
US6414028B1 (en) * 1997-11-05 2002-07-02 Nexmed Holdings, Inc. Topical compositions containing prostaglandin E1
ATE216875T1 (en) 1999-01-27 2002-05-15 Idea Ag NON-INVASIVE VACCINATION THROUGH THE SKIN
ATE216223T1 (en) 1999-01-27 2002-05-15 Idea Ag TRANSNASAL TRANSPORT OR VACCINATION WITH HIGHLY ADAPTABLE CARRIERS
WO2001001962A1 (en) * 1999-07-05 2001-01-11 Idea Ag. A method for the improvement of transport across adaptable semi-permeable barriers
DE10137102A1 (en) * 2001-07-30 2003-02-27 Deutsches Krebsforsch Polyvalent vaccine against diseases caused by papillomaviruses, processes for their production and their use
US20040038303A1 (en) * 2002-04-08 2004-02-26 Unger Gretchen M. Biologic modulations with nanoparticles
US7473432B2 (en) * 2002-10-11 2009-01-06 Idea Ag NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery
EP1952809B1 (en) * 2002-12-18 2017-08-02 Besins Healthcare Luxembourg SARL Formulations for the reduction of breast density with 4-Hydroxy Tamoxifen
US9173836B2 (en) * 2003-01-02 2015-11-03 FemmeParma Holding Company, Inc. Pharmaceutical preparations for treatments of diseases and disorders of the breast
AU2003100262B4 (en) * 2003-04-07 2003-09-18 Jurox Pty Ltd Stable carprofen composition
US20040258740A1 (en) * 2003-04-10 2004-12-23 Nene Labs Transdermal delivery composition
US20050208139A1 (en) * 2004-03-22 2005-09-22 Ascend Therapeutics, Inc. Chemically stable compositions of 4-hydroxy tamoxifen
JP2007532562A (en) 2004-04-07 2007-11-15 ザ ユニバーシティ オブ ジョージア リサーチファウンデーション，インコーポレイティド Glucosamine and glucosamine / anti-inflammatory mutual prodrugs, compositions and methods
US8034796B2 (en) * 2004-04-07 2011-10-11 The University Of Georgia Research Foundation, Inc. Glucosamine and glucosamine/anti-inflammatory mutual prodrugs, compositions, and methods
EP1815852B1 (en) * 2004-11-05 2017-01-25 Lead Chemical Co. Ltd. Nonaqueous preparation for percutaneous absorption containing nonsteroidal antiflammatory analgesic
KR20070086045A (en) * 2004-11-12 2007-08-27 이데아 아게 Extended surface aggregates in the treatment of skin conditions
US7919583B2 (en) * 2005-08-08 2011-04-05 Discovery Genomics, Inc. Integration-site directed vector systems
US7879344B2 (en) 2006-06-29 2011-02-01 Kimberly-Clark Worldwide, Inc. Transdermal delivery of oleocanthal for relief of inflammation
CA2674078C (en) * 2006-12-26 2012-03-20 Femmepharma Holding Company, Inc. Topical administration of danazol
US20090123504A1 (en) * 2007-11-12 2009-05-14 Kimberly-Clark Worldwide, Inc. Olive oil formulation for pain relief
US20100105140A1 (en) * 2008-07-16 2010-04-29 Fahrenkrug Scott C Plaice dna transposon system
MX2011009509A (en) 2009-03-12 2012-01-20 Advance Holdings Ltd Pharmaceutical formulation comprising ketoprofen and a polyoxyalkylene ester of a hydroxy fatty acid.
US20110003000A1 (en) * 2009-07-06 2011-01-06 Femmepharma Holding Company, Inc. Transvaginal Delivery of Drugs
EP3485881B1 (en) 2009-07-10 2024-03-13 President and Fellows of Harvard College Permanently charged sodium and calcium channel blockers as anti-inflammatory agents
US20130109674A1 (en) 2009-12-18 2013-05-02 Achelios Therapeutics Llc Methods and compositions for treating and preventing trigeminal autonomic cephalgias, migraine, and vascular conditions
MX365427B (en) * 2011-05-03 2019-06-03 Aponia Laboratories Inc Transdermal compositions of ibuprofen and methods of use thereof.
US9012402B1 (en) 2014-06-11 2015-04-21 James Blanchard Gel for topical delivery of NSAIDs to provide relief of musculoskeletal pain and methods for its preparation
SG10201902499VA (en) 2014-09-03 2019-04-29 Genesegues Inc Therapeutic nanoparticles and related compositions, methods and systems
CN107614061A (en) 2014-12-01 2018-01-19 阿科莱尔斯疗法公司 For treating the antimigraine and illness method and composition relevant with pain
CA2994545A1 (en) 2015-08-03 2017-02-09 President And Fellows Of Harvard College Charged ion channel blockers and methods for use
JP2018537503A (en) * 2015-12-16 2018-12-20 アケリオス セラピューティクス，インコーポレーテッド Methods and compositions for treating peripheral neuropathy
US10821075B1 (en) 2017-07-12 2020-11-03 James Blanchard Compositions for topical application of a medicaments onto a mammalian body surface
KR20190101140A (en) * 2018-02-22 2019-08-30 동아제약 주식회사 Pharmaceutical composition for forming film comprising NSAID
JP2022525856A (en) 2019-03-11 2022-05-20 ノシオン セラピューティクス，インコーポレイテッド Charged ion channel blockers and usage
US10786485B1 (en) 2019-03-11 2020-09-29 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
KR20210145164A (en) 2019-03-11 2021-12-01 녹시온 테라퓨틱스 인코포레이티드 Ester Substituted Ion Channel Blockers and Methods of Use
CA3129117A1 (en) 2019-03-11 2020-09-17 Bridget Mccarthy Cole Charged ion channel blockers and methods for use
US10780083B1 (en) 2019-03-11 2020-09-22 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
IL292505A (en) 2019-11-06 2022-06-01 Nocion Therapeutics Inc Charged ion channel blockers and methods for use
EP4054586A4 (en) 2019-11-06 2023-11-22 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
AU2021236130A1 (en) 2020-03-11 2022-09-22 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4393076A (en) * 1980-05-14 1983-07-12 Hisamitsu Pharmaceutical Co., Inc. Anti-inflammatory and analgesic gel composition
US5093133A (en) * 1990-01-24 1992-03-03 Mcneil-Ppc, Inc. Method for percutaneous delivery of ibuprofen using hydroalcoholic gel
US5210099A (en) * 1991-02-11 1993-05-11 American Home Products Corporation Analgesic compositions
US5527832A (en) * 1994-02-05 1996-06-18 Il-Dong Pharm. Co., Ltd. Antiinflammatory and analgesic transdermal gel
US5654337A (en) * 1995-03-24 1997-08-05 II William Scott Snyder Topical formulation for local delivery of a pharmaceutically active agent

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4525348A (en) * 1983-12-19 1985-06-25 Yoshitomi Pharmaceutical Industries, Ltd. Pranoprofen gelled ointment
US4923898A (en) * 1984-12-26 1990-05-08 Analgesic Associates Analgesic, anti-inflammatory and skeletal muscle relaxant compositions comprising non-steroidal anti-inflammatory drugs and musculoskeletal relaxants and methods of using same
JPH06104624B2 (en) * 1986-05-07 1994-12-21 太郎 小木曽 Transdermal agent
US4771004A (en) * 1986-08-29 1988-09-13 Iprx, Inc. Method for in vitro determination of transdermal absorption
US4980378A (en) * 1988-06-01 1990-12-25 Odontex, Inc. Biodegradable absorption enhancers
US5082866A (en) * 1988-06-01 1992-01-21 Odontex, Inc. Biodegradable absorption enhancers
US5534260A (en) * 1989-02-23 1996-07-09 University Of Utah Percutaneous drug delivery system
US5210009A (en) * 1991-06-28 1993-05-11 Eastman Kodak Company Silver recovery element and process

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4393076A (en) * 1980-05-14 1983-07-12 Hisamitsu Pharmaceutical Co., Inc. Anti-inflammatory and analgesic gel composition
US5093133A (en) * 1990-01-24 1992-03-03 Mcneil-Ppc, Inc. Method for percutaneous delivery of ibuprofen using hydroalcoholic gel
US5210099A (en) * 1991-02-11 1993-05-11 American Home Products Corporation Analgesic compositions
US5527832A (en) * 1994-02-05 1996-06-18 Il-Dong Pharm. Co., Ltd. Antiinflammatory and analgesic transdermal gel
US5654337A (en) * 1995-03-24 1997-08-05 II William Scott Snyder Topical formulation for local delivery of a pharmaceutically active agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1028710A4 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6368618B1 (en) 1999-07-01 2002-04-09 The University Of Georgia Research Foundation, Inc. Composition and method for enhanced transdermal absorption of nonsteroidal anti-inflammatory drugs
WO2001002015A1 (en) * 1999-07-01 2001-01-11 The University Of Georgia Research Foundation, Inc. Composition and method for enhanced transdermal absorption of nonsteroidal anti-inflammatory drugs
EP1095659A1 (en) * 1999-10-26 2001-05-02 Deutsche Homöopathie-Union Oil-in-water emulsions stabilised by cellulose ethers as carriers for homeopathic and plant drugs
JP2003532668A (en) * 2000-05-12 2003-11-05 サノフィ−サンテラボ Pharmaceutical composition for transdermal administration of anti-inflammatory agent
EP1304992A4 (en) * 2000-08-03 2006-11-02 Dow Pharmaceutical Sciences Topical gel delivery system
EP1304992A1 (en) * 2000-08-03 2003-05-02 Dow Pharmaceutical Sciences Topical gel delivery system
EP2052714A1 (en) * 2000-08-03 2009-04-29 Dow Pharmaceutical Sciences, Inc. Topical gel delivery systems for treating skin disorders
WO2004010988A1 (en) * 2002-07-31 2004-02-05 Connetics Australlia Pty Ltd Percutaneous and perungual delivery system
WO2009012908A2 (en) * 2007-07-26 2009-01-29 Bayer Animal Health Gmbh Medicament for transdermal use on animals
DE102007034976A1 (en) 2007-07-26 2009-01-29 Bayer Healthcare Ag Medicinal products for transdermal use in animals
WO2009012908A3 (en) * 2007-07-26 2009-06-11 Bayer Animal Health Gmbh Medicament for transdermal use on animals
GB2476155A (en) * 2009-12-11 2011-06-15 Reckitt Benckiser Healthcare Int Ltd Topical NSAID formulations
EP3512498A4 (en) * 2016-09-16 2020-06-10 Achelios Therapeutics, Inc. Topical anti-inflammatory compositions
AU2017325726B2 (en) * 2016-09-16 2022-10-13 Achelios Therapeutics, Inc. Topical anti-inflammatory compositions

Also Published As

Publication number Publication date
JP2001521887A (en) 2001-11-13
BR9813947A (en) 2002-01-15
CA2309178A1 (en) 1999-05-14
IL135886A (en) 2004-09-27
TR200002159T2 (en) 2000-11-21
CA2309178C (en) 2008-04-29
HK1034898A1 (en) 2001-11-09
TW522021B (en) 2003-03-01
CN1284863A (en) 2001-02-21
IL135886A0 (en) 2001-05-20
EP1028710A1 (en) 2000-08-23
CN1198586C (en) 2005-04-27
KR100621817B1 (en) 2006-09-13
EP1028710A4 (en) 2006-03-15
KR20010031828A (en) 2001-04-16
US6083996A (en) 2000-07-04

Similar Documents

Publication Publication Date Title
US6083996A (en) Topical compositions for NSAI drug delivery
US6046244A (en) Topical compositions for prostaglandin E1 delivery
AU632655B2 (en) Method for percutaneous delivery of ibuprofen using hydroalcoholic gel
US8470886B2 (en) Topical ibuprofen formulations
US5350769A (en) Antiinflammatory gel preparation
RU2463038C2 (en) Diclofenac gel
US20030082226A1 (en) Non-steroidal antiinflammatory drug formulations for topical application to the skin
AU669492B2 (en) Fomentation containing ketorolac
EP0101178A2 (en) Topical anti-inflammatory compositions
US5795916A (en) Composition of external preparation
JP4195178B2 (en) Anti-inflammatory analgesic topical
JPH07267839A (en) Ointment composition adhesive to oral mucosa
BR112020016597A2 (en) WATER COMPOSITION, USES AT LEAST ONE ORGANIC SOLVENT, METHOD FOR PREPARING A COMPOSITION, BOTTLE AND KIT
JP7190538B2 (en) Pharmaceutical composition
WO2007099559A2 (en) Method of preparation for novel composition of 2-{(2,6 dichlorophenyl) amino] benzeneacetic acid carboxymethyl ester or 2-[2-[2-(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid and method of its use
JPH06256168A (en) Ointment base and composition for treating periodontosis using the same
CA2442479C (en) Topical compositions for prostaglandin e1 delivery
BR102018010687A2 (en) dermatological gel pharmaceutical composition comprising ibuprofen

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 135886

Country of ref document: IL

Ref document number: 98812940.X

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): BR CA CN IL JP KR MX TR

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref document number: 2309178

Country of ref document: CA

Ref document number: 2309178

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020007004899

Country of ref document: KR

Ref document number: PA/A/2000/004351

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2000 518650

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1998956603

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2000/02159

Country of ref document: TR

WWP Wipo information: published in national office

Ref document number: 1998956603

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020007004899

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 1020007004899

Country of ref document: KR