Patent Abstract:
a drug - delivery system is described which can serve as a platform for the topical delivery of a wide variety of therapeutic agents to the skin . specifically , a topical external analgesic gel contains ketoprofen , a skin penetration enhancer / cosolvent , a thickening agent and a base to adjust ph . the formulation uses a relatively small number of safe components and is easy to prepare with a high yield of finished product . the chemical stability of ketoprofen in the gel and the physical stability of the gel itself ensure a satisfactory shelf - life for the product . the gel is aesthetically pleasing and has proven to provide rapid relief of musculoskeletal pain , thereby helping to ensure patient compliance .

Detailed Description:
some examples of compositions which we have prepared and tested for their aesthetic properties as well as their efficacy in treating musculoskeletal pain are provided in table i . these examples are given in order to provide those with ordinary skill in the art with a complete disclosure and description of how to make and use the invention and are not intended to limit the scope of the invention . the compositions shown in table 1 , for a 1 kg batch , are preferably prepared according to the following procedure . a . disperse the carbopol ultrez polymer stepwise in ˜ 80 % (˜ 800 gm ) of the deionized water in a 1000 ml beaker . the edta should be dissolved here . heat the water to a maximum of 50 - 55 ° c . to speed the dispersal of the ultrez polymer . discontinue heating when dispersion of the ultrez is complete . b . when the ultrez polymer has fully dissolved pour it into a large stainless steel mixing bowl . lock the stainless steel bowl into position on a mixer . use the remaining weight of water to rinse the ultrez - containing beaker into the mixing bowl . c . dissolve the ketoprofen in the transcutol p . add this solution in small portions to the ultrez , edta , and water mixture while stirring . d . add paragon iii and the fragrance after the above mixture cools to 40 ° c . or below while continuing to mix . e . neutralize with the triethanolamine solution dropwise to a ph of 4 . 5 to 5 . 3 and continue mixing for 10 min , until uniform . f . record the ph and fill the product into labeled tubes or jars . the method of delivery of the active ingredient ( s ) involves the application of the gel compositions to the skin over the desired site of action ( e . g ., the painful area ) by inunction for a sufficient period of time to provide the desired local effect . all of the example compositions ( and many other closely - related compositions ) have been found to be aesthetically pleasing and to provide rapid relief of musculoskeletal pain . the repeated use of these compositions over many years has not resulted in any undesirable systemic side effects and did not produce any noticeable tissue damage , irritation , or sensitization . the compositions described here may be used for the topical delivery of a wide variety of therapeutic agents either alone or in combination , including both hydrophilic and hydrophobic moieties . in addition to ketoprofen , other preferred nsaids are diclofenac sodium , naproxen , ketorolac and piroxicam . salts , esters , amides , prodrugs , and other derivatives of the nsaids may be used if they are suitable pharmacologically . for those nsaids that are chiral in nature the drug may be incorporated into the invention either as the racemate or an enantiomerically pure form . 1 . the invention contains 3 - 30 % pharmaceutical grade dgme , preferably transcutol p ( preferably about 5 . 0 %), which is not present in any of the nsaid - containing products currently on the market anywhere in the world . 2 . the invention provides a rapid onset of effect as a result of the enhancement of the skin penetration of the nsaid by the dgme , preferably transcutol p . 3 . the invention provides a prolongation of the therapeutic effect due to the formation of intracutaneous depots containing the nsaid in the subcutaneous tissues as a result of the action of the dgme , preferably transcutol p . 4 . the invention contains no lower alcohols ( typically ethanol , isopropanol , or mixtures thereof ) which are volatile and can evaporate on the skin following application , or during storage in the container over time , or which can irritate the skin when applied topically and thus are unsuitable for applying directly to broken or damaged skin areas . 5 . the “ universal ” nature of the carbomer polymers used in this invention ( 51 ) provides the properties desired over a diverse range of product types . such properties include clarity , highly - efficient viscosity , non - tacky feel , rich buttery texture , and ease of preservation compared to many other “ natural ” thickening agents . 6 . the easy dispersability of these newer carbomer polymers derivatives ( the ultrez series ) speeds up significantly the overall manufacturing process by reducing greatly the wetting time and the tendency toward clumping observed with previous carbomer polymers . 7 . the low viscosity of aqueous carbomer ultrez polymer dispersions enables the following important processing and / or cost saving advantages : ( i ) unlike the traditional carbomer polymers , it is possible to prepare very concentrated stock solutions with carbopol ® ultrez polymers . when a master batch is needed , a single batch at a concentration as high as 5 % can be made more easily and more rapidly , saving valuable production time . ( ii ) if the master batch of unneutralized carbomer polymer stock dispersion needs to be pumped and transported along pipe lines within the production site , the low viscosity of carbopol ® ultrez polymers dispersions makes this easier to accomplish . ( iii ) because of the low viscosity of concentrated carbopol ® ultrez polymers stock dispersions , less foam is created during the initial stages of mixing due to less entrapment of air . also , for the same reason , the subsequent mixing of additional ingredients is easy , reducing the processing time . the low dispersion viscosity at high concentrations of carbopol ® ultrez polymer dispersions is primarily due to enhanced particle behavior of the resin . carbopol ® ultrez polymer resin thickens systems primarily because of its higher rigidity rather than its swelling behavior . in traditional carbomer polymer dispersions the situation is exactly the reverse and hence the higher viscosities of their dispersions . ( iv ) the unique balance between the swelling and the particle - like behavior in a carbopol ® ultrez polymer makes it possible for a formulator to create everything from thin lotions to thicker creams using only a single rheology modifier . current practice in the personal care industry is to use different carbomer polymers for lotions , creams and gels depending on the desired viscosity of the final product . the special properties of the carbopol ® ultrez polymers result in additional performance benefits : the dual nature of viscosity building by the carbopol ® ultrez polymer , i . e ., thickening by swelling at concentrations ( c ) close to its overlap concentration ( c *) 1 , and , thickening by its rigid particle nature at higher concentrations , leads to some interesting cost - efficiency considerations . it has been observed , for example , that certain personal care product formulations prepared with carbopol ® ultrez polymers have 10 , 20 or even 40 % more viscosity than those prepared with traditional carbomer polymers , like carbopol ® 934 , at the same polymer concentration . conversely , a significantly lower concentration of carbopol ® ultrez polymer in the formulation is required compared to traditional carbomer polymers to reach the same final viscosity . 1 the overlap concentration ( c *) represents an average segment concentration of individual polymer coils . such concentration is determined by the mass of the macromolecule and the volume that it occupies in solution . where m is the molar mass of the particle , v m its volume and n a is avogadro &# 39 ; s number . experimentally a marked change in behavior is observed when a certain concentration , c *, is exceeded . at c & lt ; c * the properties of individual macromolecules can be studied but at c & gt ; c * the individual macromolecules are no longer well separated from each other , and only an ensemble of many macromolecules is observed . the concentration c * is still very low ( ˜ 10 − 2 g / ml ) and the solution can certainly be considered “ dilute ”. however , c * separates two dilute solution regimes of remarkably different behavior . to distinguish the moderately dilute solutions from the very dilute solutions the expression semidilute was coined to describe those that are moderately dilute . the concentration c * has a simple physical meaning . in dilute solution the coils are highly swollen , and the mean segmental concentration within a particle c int is rather low (& lt ; 10 − 2 g / ml ). when the polymer concentration is increased , a stage is reached at which c = c int = c *. at this point the segments of the coils start to overlap and become entangled . for this reason c * is called the overlap concentration . of course , the over - all concentration can be increased beyond c * but this results in drastic changes in the solution properties . reference : aberle , t . and burchard , w . ( 1997 ), starches in semidilute aqueous solution . starch / stärke , 49 : 215 - 224 . doi : 10 . 1002 / star . 19970490602 . carbopol ® ultrez polymers swell significantly less than traditional carbomer polymers and their thixotropic index 2 is generally higher than those of traditional carbomer polymers . this unique combination of fundamental properties results in less tackiness of personal care products formulated with carbopol ® ultrez polymers compared to products thickened with older , traditional carbomers . this improved , less tacky , feel has been observed consistently in formulations prepared in our laboratory using the four carbopol ® ultrez carbomer polymers , i . e ., ultrez 10 , 20 , 21 and 30 . 2 the carbopol polymer systems are shear - thinning or pseudoplastic in nature , i . e ., their viscosity ( a measure of resistance to flow ) decreases as a shear stress is applied . an example of the application of a shear stress is as simple as shaking a bottle containing the polymer . a more sophisticated way to apply a shear stress is to use a flat round plate mounted horizontally on a vertical rod ( spindle ). the spindle is then placed into the material to be measured , and rotated at a defined speed for given time interval . this principle in used to measure viscosity in well - known devices such as the brookfield viscometer . the thixotropic index is determined by measuring the viscosity of a sample at an initial ( low ) speed of rotation of the spindle ( i . e ., at a low applied shear stress ) and then at a second ( higher ) speed of rotation ( i . e ., a higher applied shear stress ). the second speed is typically 10 times the initial speed . a shear - thinning material will exhibit a lower viscosity as the applied shear stress ( i . e ., speed of rotation of the spindle ) is increased . thus for shear - thinning systems like the carbopols the thixotropic index will be a numerical value greater than 1 . this index therefore provides a relative measure of the material &# 39 ; s ability to hold its shape . 1 . dgme , preferably transcutol p is able to dissolve a wide variety of nonpolar and hence poorly water - soluble drugs . the drug solution is then miscible with the polar water phase of the formulation . in addition , dgme , preferably transcutol p is much less volatile than commonly used solvents such as ethanol and isopropanol and thus is much less likely to evaporate when the formulation is applied to the skin or when the product is stored in its container over several months of use . these unique properties of dgme , preferably transcutol p as a formulation adjuvant simplify greatly the method of manufacture of the gel compared to , for example , an emulsion whose manufacture is much more technically demanding and labor intensive . in addition , the low solubility of nsaids in the oil phase of emulsions can lead to precipitation of drug during storage , resulting in a reduced efficacy and a shortened shelf life . dgme , preferably transcutol p is able to dissolve a wide variety of hydrophobic materials ( e . g ., drugs ) which remain miscible when mixed with the aqueous gel components and thus remain largely in solution and form an aesthetically pleasing gel . 2 . the principles embodied in the invention provide a generally useful drug delivery platform that can be applied to the preparation of topical formulations for a wide variety of poorly water - soluble drugs including , but not limited to , antifungals , anti - infectives , steroids , retinoids , cytostatics , antivirals , etc . 3 . the presence of the relatively non - volatile dgme , preferably transcutol p ( bp 196 ° c .) permits the amount of the more - volatile alcoholic cosolvent components , typically ethanol ( bp 78 . 4 ° c .) or isopropanol ( bp 82 . 5 ° c . ), present in most of the commonly used similar gel preparations , to be reduced considerably or completely eliminated . this feature prevents the gel from drying out in its container or on the skin too rapidly such that a precipitate of some of the least soluble ingredients ( e . g ., the nsaid ) is avoided . this is an important consideration since transcutaneous penetration of the drug from this unsightly layer of undissolved drug is very low or non - existent . 4 . the addition of dgme , preferably transcutol p permits the preparation of a non - greasy , non - staining gel devoid of any unpleasant odor . any perceived odor will be slight and can be easily masked by the addition of a small amount of fragrance . 5 . the addition of dgme , preferably transcutol p enhances the penetration of the nsaid through the stratum corneum ( barrier ) layer of the skin into the subcutaneous tissues where the formation of intracutaneous depots of active ingredient can occur , a process known as local enhanced topical delivery or letd . this provides for a rapid onset and a prolonged duration of the therapeutic effect . 6 . ketoprofen was proven to be chemically stable in the formulation for over 210 days at elevated temperature ( 40 ° c .) which indicates that a 2 year shelf life at room temperature ( 23 ° c .) is attainable . 7 . the formulation is physically stable and no phase separation , syneresis , or significant drying out was observed in actual samples used by patients that were stored in large ( 1 lb .) jars at room temperature for more than 8 years . obviously , the use of tubes with much smaller openings than the jars would provide for at least equal ( likely greater ) long - term stability during use by patients . 8 . many topical gels containing carbomer polymers are neutralized to a final ph of 6 . 5 - 7 . 0 to “ achieve a maximum viscosity ”. if one examines carefully the ph vs . viscosity profiles of the carbomer polymers used here it is evident that a viscosity at or near the maximum is maintained from about ph 4 . 5 to 9 . the present invention utilizes a ph in the preferred range 4 . 5 to 5 . 3 in order to retain a sufficiently high viscosity while also maximizing the fraction of ketoprofen in its unionized form . the unionized ( non - polar ) form of the drug is better able to partition out of the aqueous ( polar ) gel vehicle into and through the relatively non - polar stratum corneum more readily than the ionized form . the composition of the present invention has numerous advantages and features , including : 1 . the composition blends into the skin rapidly and provides relief of inflammation and pain in rheumatoid arthritis , osteoarthritis , soft tissue injuries , strain , sprain and sports injuries . 2 . the composition is safe and effective . 3 . the composition uses a relatively small number of commonly used and safe components and is easy to manufacture . 4 . the composition provides a consistently high yield of finished product , typically & gt ; 95 % for 1 kg batches . 5 . the composition is relatively inexpensive to manufacture , as a result of factors 3 and 4 listed above . 6 . the composition can be applied for an extended period , e . g ., 10 - 12 days , without any significant risk of harmful effects . 7 . the composition provides an increased duration of therapeutic effect due to the formation of intracutaneous depots in the skin containing the active ingredient ( s ). 8 . the composition is pharmaceutically elegant , i . e ., it is aesthetically pleasing to the touch , has no runny consistency or greasy feel , and has no undesirable odor . 9 . the composition is easily removed from skin or clothing by washing with water . 10 . the composition does not stain clothing . 11 . the composition does not cause irritation , dryness , or other undesirable changes to the skin . 12 . the composition is more physically stable than an emulsion and eliminates the possibility of any creaming or cracking that can occur with emulsions . 13 . the composition avoids the need for a surfactant which is essential when preparing an emulsion formulation . this is advantageous as surfactants often cause skin irritation , especially on broken skin surfaces . 14 . the lower blood levels of nsaid following topical application of the composition of the present invention compared to those observed following oral dosing ( typically 5 % or less ) results in a relatively low potential for the patient to experience the gastrointestinal , cardiovascular , or renal toxicities that can be observed following oral dosing . 15 . the composition allows the active ingredient ( drug ) contained therein to avoid significant metabolism in the gut or by the liver ( the so - called “ first - pass ” effect ) because the drug does not pass through gut or the liver before exerting its therapeutic effect . 16 . the lower blood levels of nsaid following topical application of the composition of the present invention compared to those observed following oral dosing results in a relatively low potential for drug interactions with other therapeutic agents being used by the patient . various changes may be made to the foregoing invention without departing from the spirit and scope thereof . 1 . gavura , s ., anti - inflammatory drugs : a closer look at the risks , science - based medicine , mar . 15 , 2013 . 2 . meek , i . l ., van de laar , m . a . f . j . and vonkeman , h . e ., non - steroidal anti - inflammatory drugs : an overview of cardiovascular risks , pharmaceuticals , 3 : 2146 - 2162 ( 2010 ). 3 . bystrianyk , r ., more hospitalized from nsaid bleeding than all american war casualties , health sentinel , 16 : 00 ( jan . 10 , 2010 ). 4 . merck announces voluntary worldwide withdrawal of vioxx ®, merck and co ., inc ., whitehouse station , n . j ., sep . 30 , 2004 . 5 . smith , a ., pfizer pulls bextra off the market , cnn money , apr . 7 , 2005 . http :// money . cnn . com / 2005 / 04 / 07 / news / fortune500 / bextra / 6 . mcgettigan p , henry d ., use of non - steroidal anti - inflammatory drugs that elevate cardiovascular risk : an examination of sales and essential medicines lists in low -, middle -, and high - income countries , plos med . 10 ( 2 ): feb . 12 , 2013 . e1001388 . doi : 10 . 1371 / journal . pmed . 1001388 7 . knox , r ., world &# 39 ; 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