this invention relates to compositions of a drug with a water soluble polymer which has been treated with a wetting sufficient amount of a wetting agent selected from anionic and cationic surfactants . in preferred embodiments the composition is a solid , usually a powder , which is then compounded into suitable solid dosage forms for oral administration . griseofulvin is a known antibiotic which has been found useful in the treatment of certain fungus diseases of plants , man and animals . griseofulvin as discussed in the background of this invention is also known as a poorly soluble or water soluble drug , which in vivo provides a low order of bioavailability when administered orally . thus the composition of the instant invention is particularly useful for griseofulvin and drugs of a similar nature such as certain steroids and antibiotics which due to their low aqueous solubility and / or high melting point are poorly absorbed . illustrative of such drugs are medrogestone ; progesterone ; estradiol ; 10 , 11 - dihydro - 5h - dibenzo [ a , d ] cycloheptene - 5 - carboxamide ; 5h - dibenzo [ a , d ] cycloheptene - 5 - carboxamide and the like . the compositions of this invention , as will soon be appreciated , further permit the formulation of solid dosage forms which may contain high concentrations of the particular drug , such as griseofulvin , with no concomitant loss of bioavailability usually associated with such high concentrations . these compositions thus allow the preparation of elegant solid dosage forms . the compositions of this invention are also resistant to agglomeration of the drug particles or the tendency of the drug in storage to produce undesirable crystal formation which adversely affects bioavailability of the drug . polymers useful in this invention include water soluble polymers which are nontoxic and pharmacologically acceptable , particularly for oral administration . illustrative of polymers , found suitable in this invention include polyvinylpyrrolidone , hydroxypropyl methyl cellulose , hydroxypropyl cellulose , methyl cellulose , block co - polymers of ethylene oxide and propylene oxide , and polyethylene glycol . generally these polymers are commercially available over a broad range of average molecular weights . for example , polyvinylpyrrolidone ( pvp ) is a well known product produced commercially as a series of products having mean molecular weights ranging from about 10 , 000 to 700 , 000 . prepared by reppe &# 39 ; s process : 1 , 4 - butanediol obtained in the reppe butadiene synthesis is dehydrogenated over copper at 200 ° forming γ - butyrolactone ; reaction with ammonia yields pyrrolidone . subsequent treatment with acetylene gives the vinyl pyrrolidone monomer . polymerization is carried out by heating in the presence of h 2 o 2 and nh 3 . debell et al ., german plastics practice ( springfield , 1946 ); hecth , weese , munch . med . wochenschr . 1 943 , 11 ; weese , naturforschung & amp ; medizin 62 , 224 ( wiesbaden 1948 ), and the corresp vol . of fiat review of german science . monographs : general aniline and film corp ., pvp ( new york , 1951 ); w . reppe , polyvinylpyrrolidon ( monographie zu &# 34 ; angewandte chemie &# 34 ; no . 66 , weinheim / bergstr ., 1954 ). generally available commercial grades have average molecular weights in the range of 10 , 000 to 360 , 000 , for example , general aniline and film corporation ( gaf ) markets at least four viscosity grades available as k - 15 , k - 30 , k - 60 , and k - 90 which have average molecular weights of about 10 , 000 , 40 , 000 , 160 , 000 and 360 , 000 , respectively . the k - values are derived from viscosity measurements and calculated according to fikentscher &# 39 ; s formula ( kline , g . m ., modern plastics 137 no . 1945 ). similar commercial products are available from basf - wyandotte . selection of a particular polymer with its characteristic molecular weight will in part depend on its ability to form suitable dosage forms with the particular drug . thus , in preparing solid dosages , whether in powder , tablet or capsule units , the composition of this invention should be readily grindable or pulverizable , or in the form of free - flowing powders . a second consideration in the selection of a particular polymer derives from the limitations inherent in the use of specific equipment with polymers of increasingly higher viscosity . for example in forming the drug - polymer solution or mixture , complete dissolution or mixing could be inhibited utilizing blenders , mixer or the like , which are inadequate by reason of low shear or proper baffles to form a uniform and homogeneous drug - polymer solution or mixture . depending on the process employed for forming of the drug - polymer mixture , another consideration in the selection of a particular polymer is that the polymer be mutually soluble in solvents for the particular drug . the wetting agents found most suitable for the present invention are those selected from anionic or cationic surfactants . in addition , to those cited in the summary of this disclosure , other suitable surfactants of the anionic variety are illustrated by sodium stearate , potassium stearate , sodium oleate and the like . the compositions of this invention are prepared in a step by step process . in the first step , a mixture or solution of the drug witht the water soluble polymer is formed . the mixture can be formed in a solvent or solvent mixture which is a mutual solvent for both the drug and the polymer . alternatively , the drug - polymer , solvent mixture can , at this stage , be coated onto lactose . where the drug and the polymer are not subject to degradation at elevated temperatures , the drug - polymer mixture may also be formed by melt mixing . any volatile solvent in which the drug is soluble is suitable for forming the drug - polymer mixture . for griseofulvin , suitable solvents would include methylene chloride , methylene chloride - ethanol , chloroform , acetone , methyl ethyl ketone and combinations thereof . the most suitable polymer for forming the melt mixture with a drug such as griseofulvin is hydroxypropyl cellulose . after the drug - polymer mixture or solution has been formed in a solvent it is dried by spray - drying , flash evaporation or air drying . commercially , spray - drying is most practical since the dried mixture is already in powder form . in the case of the melt mixture drying the drug - polymer mixture is defined as cooling . the melt - mix product is then ground or milled into powder form in preparation for the next step ; grinding or milling may also be necessary for dried solvent formed mixtures . the powdered drug - polymer mixture is then treated with a wetting sufficient amount of a primarily aqueous wetting solution containing a wetting agent selected from anionic and cationic surfactants . this wetting treatment is accomplished by forming a slurry , wet granulation or paste mixture of the powdered drug - polymer with the wetting solution . the wetting solution treatment can be achieved with small incremental additions of the wetting solution or a larger single - shot treatment . the wetting solution treatment apparently fulfills two roles : crystallization of any amorphous regions into ultramicrosize crystals , and the breakup of clusters of such crystals so that they disperse spontaneously when exposed to water . also , the role of the primarily aqueous solution for the wetting agent treatment is to distribute the wetting agent to surfaces of the drug , whether or not the drug is amorphous or crystalline . when the employment of more than one polymer is desired , separate drug - polymer mixtures for each polymer are usually prepared which are then initimately blended with each either in dry form prior to or after the wetting solution treatment . the treated mixture is then dried as earlier described and , if necessary , it is milled , screened or ground prior to formulating into suitable dosage forms with pharmaceutically acceptable excipients . it will be again appreciated by those skilled in the art that while the invention is illustrated with particularly water insoluble drugs , the composition and method of this invention is also applicable to more soluble drugs in need of enhanced bioavailability . in such instances a broader range of solvents and polymers including the natural gums may be employed to form the drug - polymer mixture . the concentrations of drug found useful in the drug - polymer mixture of this invention range from the lowest therapeutically effective amount of the drug up to about 90 to 95 % of the drug . thus , in griseofulvin - polymer mixtures , the concentration of griseofulvin ranges from about 0 . 1 % by weight to about 90 - 95 % by weight . in order to form pharmaceutically elegant dosage forms for high dose drugs , the concentration of the drug should be at least 50 % by weight of the drug - polymer mixture . in especially preferred embodiments the concentration of drug in the drug polymer mixture will range from about 50 % to about 80 % by weight . the required concentration for the wetting agent ( or surfactant ) in the primarily aqueous wetting solution is a wetting sufficient amount . this amount further depends on whether incremental or single - shot wetting treatments are employed and on whether a slurry or paste treatment is contemplated . generally , small incremental treatments will require less wetting agent than a larger single shot treatment and a paste treatment will require more wetting agent than a slurry . in any case , it has been found that satisfactory results are obtained when the amount of wetting agent comprises from about 0 . 025 % to about 2 . 0 % by weight of the dried drug polymer mixture and preferrably from about 0 . 1 % or 0 . 2 % to about 1 . 0 % by weight . while higher concentrations of the wetting agent may be satisfactorily employed , no additional advantages in terms of dissolution and / or bioavailability are obtained . it has also been found that when a griseofulvin - polymer , melt mixture has been wetted and crystallized from an aqueous sorbitol solution , enhanced dissolution rates was obtained , however the rate of dissolution was still less that those mixtures treated with a wetting agent . the rate of dissolution of the powdered materials was determined by one of three methods . all three methods gave equivalent results and only the results of method 1 outlined below are used herein unless otherwised noted . method ( 1 ) a sample containing 20 mg of griseofulvin was dissolved into 1 liter of a 0 . 02 % polysorbate 80 aqueous solution at 37 ° c . the solution was monitored by a flow cell in a spectrophotometer set at 295 nm . method ( 2 ) a sample containing 500 mg griseofulvin was dissolved in 10 liters of 0 . 15 % sodium lauryl sulfate in water at 37 ° c . method ( 3 ) a sample containing 125 mg griseofulvin was dissolved in 24 liters of water at 37 ° c . for examples 2 - 5 the wetting agent solution employed was as follows : 2 . 5 g of sodium lauryl sulfate ( sls ) were dissolved into 500 ml of a mixture of 100 ml of water and 400 ml of ethyl alcohol or 0 . 25 g of sodium lauryl sulfate were dissolved into 50 ml of a mixture of 10 ml of water and 40 ml of ethyl alcohol . this example describes the preparation of ultramicrocrystalline griseofulvin . the method consists of flash evaporation of a solution containing 10 g of griseofulvin and 10 g of polyvinylpyrrolidone ( povidone ® k - 30 , u . s . p .- from gaf corp .) dissolved in 200 ml of methylene chloride . the evaporation was done on a rotating evaporator at 35 °- 45 ° c . in a closed system ( vacuum ). about 4 - 5 ml of the solution to be evaporated was placed in a 100 ml round bottom flask , then placed on the evaporator . upon evaporation of solvent , the material was deposited onto the wall of the flask . the dried material was found to be amorphous by x - ray diffraction . next , this amorphous material was treated with the sls solution . to 2 g of powder , 0 . 125 ml of the solution was added with constant mixing and the solvent was allowed to dry . this was repeated six more times until a total of 0 . 875 ml of solution had been added . microscopic observation and dissolution data showed that ultramicrocrystalline griseofulvin was formed by this method and has a much faster dissolution rate into water at 37 ° c ., than microsized griseofulvin or untreated amorphous material table 1______________________________________ dissolution profile of griseofulvin into water at 37 ° c . thedissolved griseofulvin , unless otherwise specified , is expressedin mg / liter over an elapsed time period in minutes . sample 1 min . 2 min . 3 min . 5 min . 10 min . 14 min . ______________________________________1 11 . 2 11 . 7 11 . 9 12 . 0 12 . 2 12 . 52 2 . 5 3 . 8 4 . 8 6 . 5 8 . 7 9 . 83 1 . 6 2 . 7 3 . 4 4 . 7 7 . 0 8 . 2______________________________________ 1 - flash evaporated griseofulvin : pvp ( 50 % griseofulvin ) treated with sls solution . 2flash evaporated griseofulvin : pvp ( 50 % 3 - microsized griseofulvin table 1 -- this example describes the preparation of ultramicrocrystalline griseofulvin by coating a solution of griseofulvin and polyvinylpyrrolidone onto lactose then treating the powder with a solution of sodium lauryl sulfate . a solution was prepared by dissolving 1 g of griseofulvin and 1 g of polyvinylpyrrolidone into 8 ml of methylene chloride . all this solution was coated successively in 1 ml portions onto 2 g of lactose and allowed to dry . the material formed by this method was crystalline by x - ray diffraction . next 1 ml of the sls solution was added to the 4 g of powder and allowed to dry . microscopic observation and dissolution data showed that the griseofulvin formed by this method was ultramicrocrystalline and had a much faster dissolution rate into water at 37 ° c ., than microsized griseofulvin . table 2______________________________________sample 1 min . 2 min . 3 min . 5 min . 10 min . 14 min . ______________________________________1 10 . 8 11 . 6 11 . 8 11 . 9 12 . 0 12 . 02 7 . 0 8 . 7 9 . 7 10 . 5 11 . 5 11 . 53 1 . 6 2 . 7 3 . 4 4 . 7 7 . 0 8 . 2______________________________________ 1 - griseofulvin : pvp ( 50 : 50 ) coated onto lactose and treated with sls solution . 2griseofulvin : pvp ( 50 : 50 ) coated onto lactose . 3microsized griseofulvin this example describes the preparation of ultramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and polyvinylpyrrolidone then treating with powder with a solution of sodium lauryl sulfate . a solution of 50 g of griseofulvin and 50 g of polyvinylpyrrolidone dissolved in 2 liters of methylene chloride was spray dried at room temperature . a mixture of 1 ml of the sls solution and 2 g of the powder was dried . microscopic observation and dissolution data showed the griseofulvin formed by this method to be ultramicrocrystalline and has a much faster dissolution rate into water at 37 ° c . than microsized griseofulvin . table 3______________________________________sample 1 min . 2 min . 3 min . 5 min . 10 min . 14 min . ______________________________________1 10 . 5 10 . 7 10 . 8 11 . 0 11 . 0 11 . 02 3 . 2 4 . 4 5 . 6 8 . 1 9 . 9 10 . 43 1 . 6 2 . 7 3 . 4 4 . 7 7 . 0 8 . 2______________________________________ 1 - spray dried griseofulvin : pvp ( 1 : 1 ) treated with sls solution . 2spray dried griseofulvin : pvp ( 1 : 1 ) 3 - microsized griseofulvin this example describes preparation of ultramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and polyvinylpyrrolidone and then treating the powder with a solution of sodium lauryl sulfate . a solution containing 70 g of griseofulvin and 30 g of polyvinylpyrrolidone dissolved into 2 liters of methylene chloride was spray dried at room temperature . to 2 g of the powder , 3 / 4 ml of the sls solution was added in six 0 . 125 ml increments and dried between additions . microscopic observation and dissolution data showed that the griseofulvin formed by this method was ultramicrocrystalline and had a much faster dissolution rate into water at 37 ° c . than microsized griseofulvin . table 4______________________________________sam - ple 1 min . 2 min . 3 min . 5 min . 10 min . 14 min . 15 min . ______________________________________1 10 . 0 10 . 9 11 . 5 12 . 0 12 . 5 12 . 7 -- 2 2 . 5 3 . 9 4 . 9 6 . 5 9 . 0 10 . 4 -- 3 1 . 6 2 . 7 3 . 4 4 . 7 7 . 0 8 . 2 -- 4 1 . 9 3 . 5 4 . 6 6 . 3 8 . 6 -- 9 . 75 1 . 8 3 . 0 4 . 0 5 . 8 8 . 1 -- 9 . 36 1 . 9 3 . 1 4 . 3 6 . 0 8 . 6 -- 9 . 7______________________________________ 1 - spray dried griseofulvin : pvp ( 70 : 30 ) treated with sls solution . 2spray dried griseofulvin : pvp ( 70 : 30 ). 3microsized griseofulvin 4 - spray - dried griseofulvin : pvp treated with the nonionic polysorbate 80 . griseofulvin : pvp : nonionic ( 69 . 7 : 29 . 7 : 0 . 5 ) 5spray dried griseofulvin : pvp treated with the nonionic block copolymer of ethylene oxide and propylene oxide ( pluronic ® f77 ) griseofulvin : pvp : nonionic ( 69 . 7 : 29 . 7 : 0 . 5 ) 6spray dried griseofulvin : pvp treated with the nonionic isooctyl phenoxy polyethoxy ethanol . griseofulvin pvp : nonionic ( 69 . 7 : 29 . 7 : 0 . 5 ) table 5______________________________________dissolution profilesample 1 min . 2 min . 3 min . 5 min . 10 min . 14 min . ______________________________________1 10 . 0 10 . 9 11 . 5 12 . 0 12 . 5 12 . 72 6 . 9 8 . 7 9 . 7 10 . 4 11 . 3 -- 3 6 . 0 7 . 0 7 . 3 7 . 7 8 . 0 -- 4 1 . 6 2 . 7 3 . 4 4 . 7 7 . 0 8 . 2______________________________________ 1 - spray dried griseofulvin : pvp ( 70 : 30 ) treated 2 - dorsey laboratories &# 39 ; grispeg ( trademark ) for griseofulvin composition i peg 6000 . 3schering laboratories &# 39 ; fulvicin p / g ( trademark ) for griseofulvin composition in peg 6000 . 4microsized griseofulvin . in the samples evaluated in tables 6 - 8 , the following further describes their preparation . two grades of hydroxypropyl cellulose were used , klucel ® ef and klucel ® lf ( hercules ), the former preferred for its lower viscosity . coarse griseofulvin , spray dried lactose , sorbitol , and sodium lauryl sulfate were the other ingredients . the solvents were methylene chloride and absolute ethanol , u . s . p . grade . crystallinity of griseofulvin preparations were judged by visual microscopic observation under crossed polarizers , or by x - ray diffraction assay . a glass melting tube immersed in a hot oil bath was used to melt together various amounts of griseofulvin and klucel . after complete melting and mixing , the liquid mixture was rapidly chilled under a cold water tap , while rotating the tube horizontally so as to distribute the liquid over the inside walls . after solidification , the tube was further cooled in a dry ice bath , which fractured the product and allowed its removal from the glass tube . the chunky product was ground to a powder in a micromill . typically , an amount of powdered melt mixture was intimately mixed with an equal weight of an aqueous solution containing , by weight , about 22 % sorbitol and 13 % ethanol . this was vigorously mixed and worked with a spatula , until the doughy mixture acquired the consistency of a smooth cream or paste . the paste was allowed to dry , and the dry chunky product was ground in a mortar . solution for spray drying were prepared by dissolving griseofulvin and klucel in a mixture of methylene chloride and ethanol . an anhydro laboratory spray dryer no . 3 was used , and the solution was spray dried at room temperature . typically , a weight of spray dried powder ( whether amorphous or crystalline ) was intimately mixed with about 0 . 9 weight of a 1 . 5 % aqueous solution of sodium lauryl sulfate . the solution could also contain ethanol and sorbitol or lactose , but this was found to be unnecessary . the doughy mixture was vigorously mixed and worked with a spatula , until it became a smooth paste . then , about 0 . 25 weight of lactose was added , and mixed until again smooth . the paste was spread and dried at around 85 ° c . the elevated temperature coagulated the wet paste into granules , which could be stirred and mixed at times during drying , to diminish caking . the dry product was milled and passed through a 60 or 80 mesh screen . the product contained about 1 % sodium lauryl sulfate . treatment of spray dried mixtures with sodium lauryl sulfate solution , without pasting about 2 . 0 g of spray dried griseofulvin - klucel ® mixture was placed in a mortar , then treated successively with six 0 . 125 ml portions of a wetting solution , allowing enough drying between portions to prevent the powder from becoming pasty . the wetting solution contained 5 mg / ml sodium lauryl sulfate in a mixture of 4 parts ethanol - 1 part water , by volume . the final granular powder contained about 0 . 2 % sodium lauryl sulfate . crystallization of spray dried powders with sodium lauryl sulfate solution on a 1 kg scale were achieved in a hobart mixer , equipped with a small bowl and a pastry blade . lactose was added to the paste , then the mixture was spread on trays and dried at 85 ° c . the chunky , partially caked product was milled and screened . ______________________________________ spray dried mixtures of griseofulvin & amp ; hydroxypropyl cellulose ( klucel )® composition of solutionsolids griseofulvin solventcontent content volume ( g / l of (% of ratio crystallinitysolvent ) solids ) ( mecl . sub . 2 / etoh ) of product______________________________________100 50 7 / 1 mostly amorphous 50 75 9 / 1 amorphous167 75 8 . 6 / 1 crystalline200 80 7 / 1 crystalline______________________________________ table 6______________________________________dissolution profile . sam - ple 1 min . 2 min . 3 min . 5 min . 10 min . 15 min . 20 min . ______________________________________1 4 . 1 8 . 0 9 . 2 10 . 8 12 . 6 13 . 4 13 . 72 1 . 5 2 . 7 3 . 4 4 . 7 7 . 0 8 . 4 9 . 23 0 . 5 1 . 0 1 . 3 2 . 0 3 . 2 4 . 2 5 . 0______________________________________ 1 - melt mixture of griseofulvin ( 75 %) klucel ® ( 25 %), crystallized with sorbitol solution 2 - micronized griseofulvin 3 - melt mixture of griseofulvin ( 83 %) klucel ® ( 17 %), amorphous . table 7______________________________________sam - ple 1 min . 2 min . 3 min . 5 min . 10 min . 15 min . 20 min . ______________________________________1 2 . 0 3 . 6 4 . 7 6 . 5 9 . 8 11 . 4 12 . 82 2 . 0 3 . 6 4 . 7 6 . 5 9 . 2 10 . 5 11 . 83 1 . 5 2 . 7 3 . 4 4 . 7 7 . 0 8 . 4 9 . 24 0 . 8 1 . 5 2 . 0 2 . 8 4 . 7 5 . 8 6 . 5______________________________________ 1 - spray dried griseofulvin ( 75 %) klucel ® ( 25 %) mixture , amorphous . 2 - spray dried griseofulvin ( 50 %) klucel ® ( 50 %) mixture , mostly amorphous . 3 - micronized griseofulvin . 4spray dried griseofulvin ( 80 %) klucel ® ( 20 %) mixture crystalline . table 8______________________________________sam - ple 1 min . 2 min . 3 min . 5 min . 10 min . 15 min . 20 min . ______________________________________1 6 . 2 11 . 1 11 . 5 12 . 0 12 . 5 12 . 7 12 . 82 6 . 2 10 . 2 11 . 0 11 . 6 12 . 1 12 . 2 12 . 33 1 . 5 2 . 7 3 . 4 4 . 7 7 . 0 8 . 4 9 . 2______________________________________ 1 - spray dried mixture of griseofulvin : pvp ( 70 : 30 ), treated with sls solution ./ 2 spray dried mixture of griseofulvin : klucel ® ( 75 : 35 ), crystallized with sodium lauryl sulfate solution . 3micronized griseofulvin this example describes preparation of ultramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and hydroxypropyl methyl cellulose and then treating the powder with a solution of sodium lauryl sulfate . a solution containing 40 g of hydroxypropyl methylcellulose 80 g of griseofulvin and 200 ml of methanol dissolved into 2 liters of methylene chloride was spray dried at r . t . the dried material was found to be amorphous by x - ray diffraction . to 4 g of the powder , 4 ml of a solution containing 1 . 5 g sodium lauryl sulfate dissolved into 100 ml of h 2 o was mixed in , and then dried . microscopic observation and dissolution data shows that ultramicrocrystalline griseofulvin was formed by this method and has a much faster dissolution rate into water at 37 ° c ., then microsized griseofulvin or untreated amorphous material . this example describes preparation of ultramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and methylcellulose and then treating the powder with a solution of sodium lauryl sulfate . a solution containing 40 g of methylcellulose ( 15 cps ) and 120 g of griseofulvin , and 200 ml of methanol dissolved into 2 liters of methylene chloride was spray dried at r . t . the dried material was found to be partly amorphous and partly crystalline by x - ray diffraction . to 4 g of the powder , 4 ml of a 1 . 5 % sodium lauryl sulfate solution was added and mixed in . the mixture then was dried . microscopic observation and dissolution data shows that ultramicrocrystalline griseofulvin was formed by this method , and it has a much faster dissolution rate then microsized griseofulvin or untreated material . this example describes preparation of ultramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and poly ( oxypropylene ) poly ( oxyethylene ) block copolymer ( pluronic ® f77 basf wyandotte corp .) and then treating the powder with a solution of sodium lauryl sulfate . a solution containing 100 g of the block copolymer and 100 g griseofulvin dissolved into 2 liters of methylene chloride was spray dried at rt , to 4 g of the powder , 2 ml of a 1 . 5 % sodium lauryl sulfate was added , mixed and then dried . microscopic observation and dissolution data shows that ultramicrocrystalline griseofulvin was formed by this method , and it has a faster dissolution rate then microsized griseofulvin or untreated material . this example describes preparation of ultramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and polyethylene glycol and then treating the powder with a solution of sodium lauryl sulfate . a solution containing 100 g of griseofulvin and 100 g of polyethylene glycol 6000 dissolved into methylene chloride was spray dried . to 4 g of the powder , 2 ml of a 1 . 5 % sodium lauryl sulfate solution was added , mixed and dried . microscopic observation and dissolution data shows that ultramicrocrystalline griseofulvin was formed by this method , and it has a much faster dissolution rate then microsized griseofulvin or untreated material . this example describes preparation of ultramicrocrystalline griseofulvin by spray drying a solution containing griseofulvin and hydroxypropyl methylcellulose and then treating the powder with a solution of sodium lauryl sulfate . a solution containing 40 g of hydroxypropyl methylcellulose , 160 g of griseofulvin and 100 ml of ethanol dissolved into 2 liters of methylene chloride was spray dried . to 2 g of powder , 0 . 125 ml of sodium lauryl sulfate wetting solution ( see above example no . 7 ) was added with constant mixing and the solvent was allowed to dry . this was repeated five more times until a total of 0 . 750 ml of solution had been added . microscopic observation and dissolution data shows that ultramicrocrystalline griseofulvin was formed by this method and it has a much faster dissolution rate then microsized griseofulvin or untreated material . this example describes preparation of ultramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and polyvinylpyrrolidone and then treating the powder with a solution of benzalkonium chloride . a solution of 70 g of griseofulvin and 30 g of polyvinylpyrrolidone dissolved into 2 liters of methylene chloride was spray dried at rt . to 4 g of the powder , 2 ml of a 1 % aqueous solution of benzalkonium chloride was added , mixed and then dried . microscopic observation and dissolution data shows that ultramicrocrystalline griseofulvin was formed by this method , and it has a much faster dissolution rate then microsized griseofulvin or untreated material . this example describes preparation of ultramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and polyvinylpyrrolidone and then treating the powder with a solution of sodium laurate . a solution of 70 g of griseofulvin and 30 g of polyvinylpyrrolidone dissolved into 2 liters of methylene chloride was spray dried at rt . to 4 g of the powder , 2 ml of a 2 % aqueous solution of sodium laurate was added , mixed and then dried . microscopic observation and dissolution data shows that ultramicrocrystalline griseofulvin was formed by this method , and it has a much faster dissolution rate then microsized griseofulvin or untreated material . this example describes preparation of ultramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and polyvinylpyrrolidone and then treating the powder with a solution of dioctyl sodium sulfosuccinate . a solution of 70 g of griseofulvin and 30 g of polyvinylpyrrolidone dissolved into 2 liters of methylene chloride was spray dried at rt . to 4 g of the powder , 2 ml of a 1 % aqueous solution of dioctyl sodium sulfosuccinate was added , mixed and then dried . microscopic observation and dissolution data shows that ultramicrocrystalline griseofulvin was formed by this method , and it has a much faster dissolution rate then microsized griseofulvin or untreated material . this example describes preparation of ulramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and polyvinylpyrrolidone and then treating the powder with a solution of bis ( 2 - hydroxyethyl ) oleylamine . a solution of 70 g of griseofulvin and 30 g of polyvinylpyrrolidone dissolved into 2 liters of methylene chloride was spray dried at rt . to 4 g of the powder , 2 ml of a 2 % aqueous solution of bis ( 2 - hydroxyethyl ) oleylamine was added , mixed and then dried . microscopic observation and dissolution data shows that ultramicrocrystalline griseofulvin was formed by this method , and it has a much faster dissolution rate then microsized griseofulvin or untreated material . table 9__________________________________________________________________________the results of dissolution studies on the samples prepared by examples7 - 15are listed below . the unit of expression for this table is percent ofsaturation achievedin time expressed in minutes . wt . % wet - gris - poly - ting eoful - percent of saturation - time min . polymer wetting agent mer agent vin 1 2 3 4 5 10 15 20 25__________________________________________________________________________none - griseoful - none none none 100 % 14 . 8 22 . 3 30 . 3 36 . 8 42 . 6 64 . 5 76 . 1 83 . 1 86 . 5vin microsizedpolyvinyl - sodium lauryl 49 . 9 0 . 2 49 . 9 92 . 9 99 . 2 100 . 6 101 . 3 101 . 9pyrrolidone sulfatepolyvinyl - sodium lauryl 29 . 9 0 . 2 69 . 9 91 . 6 97 . 0 98 . 8 99 . 4 99 . 6 100 . 0pyrrolidone sulfatepolyvinyl - sodium lauryl 9 . 9 0 . 2 89 . 9 60 . 7 70 . 0 89 . 0 83 . 9 85 . 8 91 . 6 93 . 5 94 . 8 95 . 6pyrrolidone sulfatepolyvinyl - benzalkonium 29 . 8 0 . 5 69 . 7 75 . 7 87 . 2 92 . 6 95 . 3 97 . 0 99 . 3 100pyrrolidone chloridepolyvinyl - dioctyl sodium 29 . 8 0 . 5 69 . 7 86 . 5 92 . 9 95 . 5 96 . 8 97 . 4 98 . 3 99 . 8pyrrolidone sulfosaccinatepolyvinyl - sodium laurate 29 . 7 1 . 0 69 . 3 53 . 5 65 . 2 72 . 3 77 . 4 81 . 9 90 . 3 94 . 8pyrrolidonepolyvinyl - bis ( 2 - hydroxy - 29 . 7 1 . 0 69 . 3 74 . 2 83 . 9 88 . 6 91 . 6 93 . 2 97 . 4 100 . 00 100 . 6pyrrolidone ethyl ) oleyl aminehydroxypropyl sodium lauryl 24 . 9 0 . 2 74 . 9 85 . 4 93 . 2 96 . 7 98 . 3 99 . 3 101 . 9cellulose sulfatehydroxypropyl sodium lauryl 19 . 9 0 . 2 79 . 9 61 . 9 71 . 6 77 . 4 81 . 5 84 . 5 94 . 2 99 . 4 101 . 9 109 . 0cellulose sulfatehydroxypropyl sodium lauryl 32 . 8 1 . 5 65 . 8 36 . 8 49 . 0 57 . 4 69 . 8 67 . 7 88 . 4 101 . 3 108 . 4 112 . 9methyl cellulose sulfatepolyethylene sodium lauryl 49 . 6 0 . 7 99 . 6 71 . 2 83 . 2 89 . 6 92 . 9 94 . 5 98 . 3 99 . 4 99 . 6glycol sulfatepolyoxyethylene sodium lauryl 44 . 6 0 . 7 49 . 6 43 . 2 56 . 7 63 . 8 68 . 6 72 . 3 81 . 3 85 . 4 87 . 7 89 . 0polyoxypropylene sulfatecopolymer__________________________________________________________________________ * saturation 11 . 6 mg liter . the relative bioavailability of the composition of this invention with two different polymer mixtures and that of one marketed ultramicrosize griseofulvin dosage form was studied in humans . the urinary excretion of the major griseofulvin metabolite 6 - desmethyl griseofulvin ( 6 - dmg ) was determined for all three dosage forms following the administration of 250 mg of griseofulvin ( in the form of 125 mg tablets ) to 15 healthy adult volunteers divided into three groups using a crossover experimental design . the total tablet weight for each of the 125 mg dosages was 350 mg . the compositions of the invention were represented by spray dried griseofulvin mixtures with either polyvinylpyrrolidone or hydroxypropyl cellulose both treated with sls . the marketed product evaluated was schering &# 39 ; s fulvicin ® p / g which is perceived as providing maximum bioavailability or absorption following oral administration . the results indicated that there were no statistically significant differences between the 3 dosage forms evaluated . the cumulative mean for all groups expressed in mg of either free or total 6 - dmg found in the urine for each of the three dosages was as follows : ______________________________________ gris - hydroxypropyl marketed gris - pvp cellulose product free total free total free total______________________________________0 - 24 hours 48 : 6 75 . 8 50 . 3 81 . 1 48 . 9 76 . 724 - 48 hours 19 . 1 30 . 0 20 . 7 33 . 3 19 . 5 37 . 10 - 48 hours 68 . 7 105 . 8 71 . 0 114 . 4 68 . 4 113 . 8______________________________________ in a second bioavailability study conducted with 4 healthy adult volunteers , dosage forms containing 500 mg of micronized griseofulvin were administered in the form of a single tablet or 2 capsules each containing 250 mg of micronized griseofulvin . since griseofulvin is not a dose dependent drug , twice the amount of the 6 - dmg metabolite should be excreted over that of a 250 mg dosage of griseofulvin . ______________________________________ 500mg griseofulvin 500mg griseofulvin tablet as 2 × 250mg capsules free total free total______________________________________0 - 24 hours 34 . 4 35 . 5 38 . 0 54 . 724 - 48 hours 63 . 5 104 . 2 64 . 4 102 . 80 - 48 hours 97 . 9 157 . 9 102 . 4 157 . 5______________________________________ typical direct compression tablet formulations may be prepared as follows for 125 mg dosage forms having a final tablet weight of 350 mg . ______________________________________a . 1 . griseofulvin at 59 . 5 % in mixture with hydroxypropyl cellulose , sls treated 210 . 0 g2 . microcrystalline cellulose 87 . 0 g3 . lactose , edible 32 . 0 g4 . sodium starch glycolate 17 . 5 g5 . magnesium stearate u . s . p . 3 . 5 g theoretical tablet weight 350 mg . b . 1 . griseofulvin at 67 . 5 % in pvp mixture treated with sls 185 . 0 g2 . microcrystalline cellulose 87 . 0 g3 . lactose , edible 67 . 0 g4 . sodium starch glycolate 17 . 5 g5 . magnesium stearate 3 . 5 g theoretical tablet weight 350 g______________________________________ in both a and b , ingredients 1 - 4 were blended together until uniform , passed through a screen , blended with ingredient 5 and compressed at the correct tablet weight . the dissolution profile for the compressed tablets demonstrated further that there was no significant difference in dissolution for the formulated tablet as compared with the unformulated powdered material .
novel compositions comprising wetted mixtures of poorly soluble drugs with water soluble polymers useful in increasing bioavailability are disclosed .