CA1204665A - Therapeutic compositions with enhanced bioavailability - Google Patents

Abstract

A B S T R A C T

Novel compositions comprising wetted mixtures of poorly soluble drugs with water soluble polymers useful in increasing bioavailability are disclosed.

Description

s THERAPEUTIC COMPOSITIONS WITH ENHANCED BIOAVAILABILITY

BACK~ROIJND OF THE INVENTION
_ 1. Field of the Invention.

This invention relates to compositions of poorly soluble or water insoluble drugs which provide poor bioavailability or are irregularly absorbed following or~l administration of their solid dosage forms. More specifically, the herein disclosed invention relates to new compositions of matter containing poorly soluble or water insoluble drugs, a non-toxic water soluble polymer ~nd a wetting agent. The invention further relates to a process for preparing and a method for using the disclosed compositions which compositions provide a high order of drug bioavailability. In the main, the invention will be illustrated with the known antifungal griseofulvin.

2. Description of the Prior Art.

Many drugs give an incomplete and irregular absorption when taken orally, particularly poorly water soluble or water insoluble compounds such as griseofulvin and many steroids. One of the earlier attempts to enhance the aYailability or bioavailability of such drugs relied on mechanical micronizationof the pure compounds in order to decrease their particle size. While micronization did enhance absorption over the use of unmicronized material, absorption of the drug was still incomplete. Further the degree of micronization which can be achieved is limited and the micronized particles tend to ag~lomerate, thus diminishing both the solubility of the drug and its bioavailability. U.S. Patent 2,900,304 is an illustration of griseofulvin compositisns for oral or parenteral administration employing micronized drug particles.

Another approach for attempting to enhance the bioavailability of griseofulvin was studied by Marvel et al and reported in The Jq of InvestigativeDermatvlogy, 42, 197-203 (1964). Their studies related to the effect of a surfactant and particle size on the bioavailability OI griseofulvin when orally administered. Results of their studies indicated that bioavailability of the drug ..............................................................................................................................................................................................
..... .

was enhanced when administered in very dilute solutions or aqueous suspensions.
Their results further tended to confirm that enhanced bioavailability was obtained with griseofulvin having a higher specific surface area, at least when administered in full daily divided doses. With respect to the effect of the surfactant sodium lauryl sulfa~e incorporated into griseofulvin tablets, their results demonstrated some initial enhancement of bioavailability with regularly particle sized drug and very little enhancement with micronized drug in comparison to surfactant-free tablets. These investigators further reported that when the daily dose was divided, the surfactant had no enhancing effect.

Still another approach for the enhancement of drug bioavailability is represented by the work of Tachibana and Nakamura in Kolli~Zeitschrift and Zeitschrift Fur Polymere, 203, pgs. 130-133 (1965) and Mayershohn et al in the Journal of Pharmaceutical Science, 55, pgs. 1323-4 (1966). Both publications deal with the use of polyvinylpyrrolidone (PVP) for forming dispersions of a drug~ Tachibana discusses the role of PVP in forming very clilute colloidal dispersions of B-carotene in PVP. Mayersohn further prepared solid dispersions or solid solutions of griseofulvin in PVP and the reported results show dissolution rates for the drug increasing with lncreasing proportions of PVP.
This last publication further reported th~t in the absence o~ wetting agent in the dissolution medium, the enhancement of the dissolution rate is still greater.

Canadian Patent 987,588 of Riegelman et al, similarly discloses the use and process for making solid dispersions of a drug for enhancing its dissolutionrate and bioabailability. In this case the solvents employed were polyethylene glycol (PEG3 having molecular weights ranging from 4"000 to 20,000, pentaerythritol, pentaerythritol tetraacetate and monohydrous citric acid.
Riegelman postulated that these solvents provided a matrice for griseofulvin which retards crystallization during the solidification process resulting in an ultrAmicrocrystalline form of the drug with correspondingly faster dissolution.
Riegelman's results tend to support this finding of faster dissolution rates forsolid solutions of griseofulvin over those of unmicronized, non-wetted microniz-ed and wetted micronized griseofulvin. But his findings were limited to those solid solutions which contain less than 50 per cent by weight of the drug since the results demonstrated a slowing of the dissolution ra~e with higher concentrations of ~riseofulvin. Riegelman further concluded that the rate of dissolution for a composition having the same ratio of drug to solvent varies ....................................................................................................................................................................... . . .

-3-significantly depending on the method of preparation, with melt mixing atelevated temperatures in a volat;le solvent providing the preferred mode or process.

Another process for preparing ultramicrocrystalline drug particles to increase dissolution of a drug is disclosed by Melliger in Belgian Patent 772,594.
That process is characterized by preparing a s~lution of the drug~ PVP and urethane and subsequently removing the urethane. It was reported that, in general, satisfactory results were obtained using solutions in which the quantity of drug represented up to about 50per cent by weight of the quantity of PVP
present.

U.S. Patent 3,673,163 and 4,024,240 respectively are further illustrations relating to the use of PVP in solid dispersions. In the first-cited patent, coprecipitates of acronycine with polyvinylpyrrolidone were prepared in proportions weighted to the polymer to increase tile solubility of the coprecipitated acronycine. In the second-cited patent solid antibiotic dispersions containing the antibiotic designated A-32390, in proportions again weighted toward the PVP co-dispersant, were disclosed. Further examples of antibiotic combinations containing PVP are disclosed in U.S. Patent 3,577,514 wherein the PVP is used as a binding agent; and in U.S. Patents 3,485,914 and 3,499,95~, wherein the PVP is used to sustain the release of the antibiotic. P~Phas also been used as a stabilizer with nitroglycerin to retard migration between nitroglycerin tablets as disclosed in U.S. Patent 4,091,091.

With respect to processes employed in preparing certain PVP-griseofulvin compositions, Junginger in Pharnn. Ind. 39, Nr. 4 at pgs. 384-388 and Nr. 5 at pgs. 498-501 (1977), reported that spray-dried products provided systems with higher energy levels in comparison with those of simple mixtures and coprecipitates, and correspondingly greater dissolution rates~ ~ultginger further disclosed that the dissolution rates of the simple mixtures were higher when thePVP contents were increased.

In a further attempt to incre~se the bioavailability of griseofulvin, the drug was treated with small amounts of hydroxypropyl cellulose and formulated into capsules, see Fell et al, J. ~harm. Pharmac., 30, 479-482 (1978). While theformulation produced by this treatment increases the rate and extent :
. . ..................... ...........................................................................................................................................................
....................

~&S

availability of micronized griseofulvin, the authors reported th~t the treated formulation does not always lead to complete absorption from the upper intestine as was reported for the Riegelman solid disperse system with polyethylene glycol 6000.

SUMMARY OF THE INVENTION

This invention provides compositions of poorly soluble or water insoluble drugs which provide higher dissolution rates in YitrO and increased bioavail-ability of said drugs in vivo. The composition of this invention comprises a mixture or solution of the drug with a non-toxic, pharmacologically acceptable water soluble polymer wherein said mixture or solution has been treated with a minor amount of a wetting agent selected from anionic and cationic surfactants. The term mixture means the product of a melt mix or that of a dried solution.

Rxamples of suitable polymers are those selected from at least one of the group comprising polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose~ methyl cellulose, block copolymers of ethylene oxide and propylene oxide, and polyethylene ~lycol. Suitable surfactants include thoseof the anionic variety such as sodium lauryl sulfate, sodium laurate or dioctylsodium sulphosuccinate, and those of the cationic va~ety such as benzalkonium chloride, bis-2-hydroxyethyl oleyl amine or the like.

In another embodiment, the invention includes a method for treating mammals with said drugs by increasing the bioavailability of the ~rug following its administration using the cornposition of this invention.

Still a further embodiment of this invention is a method of preparing compositions with increased bioavailability in mammals from a poorly soluble or water insoluble drug. The method includes the steps of:

(a) Forming a mixture or solution of a drug with a non-toxic, pllarmaco-logically Acceptable water-soluble polymer;

(b~ drying the drug-polymer solution;

...... ....................................................................................................................................................................................
............

(c~ mixing the dried drug-polymer mixture or solution with a surface wet .ing amount of wetting agent solution wherein said agent is selected from anionic and cationic surfactants;
and (d) drying the mixture of step tc).

The method for preparingr these compositions is also usef~l as a method for preparing ultramicrocrystalline griseofulvin.

While the invention is illustrated with poorly soluble or water insoluble drugs, and particularlv griseofulvin, it will become apparent to those skilled in the art that the compositions and method of this invention are also suitable forother drugs which while relatively soluMe have a tendency to agglomerate or crystallize in storage, or after formulation into pharmaceutical dosage forms.

DETAIL~D DESC~IPTION OF THE INVENTIOM

This invention relates to compositions of a drug with ~ water soluble polymer which has been treated wlth 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 8 known antibiotic which has been ~ounà 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 insoluble 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 o a similar nature su~h as certain steroids and antibiotics which due to their low aqueous solubility and/or high melting point are poorly absorbed. Tllustrative of such drugs are medrogestone;
progesterone; estradiol; 10, l~dihydro-5H-dibenzola,d] cycloheptene-5-carbox-amide; 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 ....................... .................................... .. ......... .. . . ......... .

~2~6~i 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 useflll in this invention include water soluble polymers which are non-toxic and pharmacologically acceptable, particularly for or~l a~
ministration. Illustrative of polymers, found suitable in this invention includepolyvinylpyrrolidone, hydroxypropyl methyl celluloseJ hydroxypropyl cellulose, methyl cellulose, block c~polymers of ethylene oxide and propylene oxide, and polyethylene glycol.

Generally these polymers are commercially availaMe over a broad range of average molecular weights. For example, polyvinylpyrrolidone (P~P) is a wcll known product produced commercially as a series of product~ having mean moleoular weights ranging from ~bout 10,000 to 700,000. Prepared by Reppe's process: 1,4-butanediol obtained in the Reppe butadiene synthesis is dehydro-genated over copper at 200 forming ~ -butyrolactone; reaction with ammonia yields wrrolidone. Subsequent treatment with acetylene gives the vinyl pyrrolidone monomer. Polymerization is carried out by heating in the presence of H202 and NH3. DeBell et al., German Plastics Practice (Springfield, 1946);
Hecht, Weese, Munch. Med. Wochenschr. 1943, 11; Weese, Naturforschung Medizin 62, 224 ~Wiesbaden 1948), and the corresp vol. of PIAT Review o~
German Scien~e. Monographs: General Aniline and Film Corp., PVP (New York, 1~51); W. Reppe, Polyvinylpyrro}idon (Monographie zu "Angewandte Chemie" no.
66, Weinheim/Bergstr., 1954). Generally availaMe commercial grades have average molecular weights ~n 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 rnolecular 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's formula (Kline, G.M., Modern Plastics 137 No. 1945). Similar commercial products are available from BASF-Wyandotte.

............................ . ..... ........ ..... ................ ................. ....................................................... ........ .... ..........
...... .. .

4~
--'I--Selection of a particular polymer with its characteristic molecular weight will in part depend on its ability to Iorm 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 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 surIactAnts. 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 OI this invention are prepared in a step by step process.

In the first step, a mixture or solution of the drug with 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 sub~ect to degradation At elevated ternperatures, the drug-polymer mixture m~y also be formed by melt mixing.
Any volatile solvent in which the drug is soluble is suitable for forming the drug-polymer mixture. Por 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 rnelt-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 arystalline.

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 drugs9 the composition and method of this invention is also applicable to more soluble drugs in need ofenhanced 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 wei~ht 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 809~ by weight.

The required concentration for the wetting agent (or surfactant) in the primari~y 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 satis~actorily employed, no additional advantages in terms of dissolution and/or bioavailability are obtained. It has ~Iso been foundthat when a griseofulvin-polymer, melt mixture has been wetted and crystalliz-ed from an a~ueous sorbitol solution, enhanced dissolution rates was obtained, however the rate of dissolution was still less that those mixtures treated with a wetting agent.

The invention is further illustrated by the following examples.

~xample l 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 l outlined below are used herein u~ess otherwised noted.
Method 1~ A sample contRining 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.

.

..... . .. ... . .. ...... ........ ............................................................................ ............... ... ...................................
.......... . .... . .

~2D~

Method 2) A sample containin~ 500 mg griseo~ulvin was dissolved in 10 liters of 0.159~ sodium lauryl sulfate in water at 37 C.

Method 3) A sample containing 125 mg ~riseofulvin was dissolved in 24 liters of water at 37 C.

For examples 2-5 the wetting agent solution emp1Oyed was as follows: 2.5g of sodium lauryl sulfate (SLS) were dissolved into 5D0 ml of a mfxture of 100 mlof 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.

Exam~ 2 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 - 45C 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 materiQl; was treated with the SLS solution. To 2 g OI powdsr, 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 r~te into water at 37 C, than microsized griseofulvin or untreated amorphous materiaL

Table 1- Dissolution proIile of griseofulvin into water at 37C. The dissolved griseofulvin, unless otherwise specified, is expressed in mg/liter over an elapsed time period in minutes.

, .................. .... . . . . .... .. ..... ...
.......................................................................

~2~665 1- Flash evaporated griseofulvin: PVP ~50% griseofulvin~ treated with SLS
solution.

2- Flash evaporated griseofulvin: PVP (50% griseofulvin) 3- Microsized griseofulvin Sample1 min. 2 min.3 min. 5 min.10 min. 14 min.
11.2 11.7 11.9 12.012.2 12.5 2 2.5 3.8 4.8 6.5 8.~ 9.8 3 1.6 2.7 3.4 4.7 7.0 8.2 Example 3 Table 1 - This example describes the preparation of ultramicrocrystalline griseofulvin by coatin~ a solution of griseofulvin and polyvinylpyrrolidone ontolactose then treatin~ the powder with a solution of sodium lauryl ~;ulfate~

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. Thematerial 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 dr~.
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-___ 1- griseofulvin: PVP (50:50) coQted onto lactose and treated with SLS
solution.
2- griseofulvin: PVP (50:50) coated onto lactose.
3- Microsized griseofulvin Sample1 min. 2 min.3 min. 5 min.10 min. 14 min.
10.8 11.6 11.8 ll.g~2.0 12.0 2 7.0 8.7 9.7 10.511.5 11.
3 1.6 g.7 3.4 4.7 7.0 8.2 ....

.... ....................................................... . . .. .... .. ................................................................................ . . .. .

~IL2~5 This example describes the preparation OI ultramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and polyvinylpyrrolidonethen treating the powder with a solution of sodium lauryl sulfate. A solution of50 g of griseofulvin and 50 g of polyvinylpyrrolidone dissolved in 2 liters o methylene c~oride was spray dried at room temperature. A mixture of 1 ml of the SLS solution and 2 g of the pvwder was dried. Microscopic observation and dissolution data showed the griseofulvin formed by this method to be ultramicrocrystalline and has a much faster dissolution rate int~ water at 3~ Cthan microsized griseofulvin.

Table 3 -1- Spray dried griseofulvin: PVP ~1:1) treated with SLS solution.
2- Spray dried griseofulvin: PVP
3- Microsized griseofulvin Sample 1 min2 min. 3 min.5 min.lO_min.14 min.
10.510.7 10.~11.0 ll.O 11.0 2 3~24.~ 5.68.1 9.9 10.
3 1.62.7 3.44.7 7.0 ~.2 amp~ 5 This example describes preparation of ultramicrocrystalline griseofulvin by spray drying a solution of griseofulvin and pol~inylpyrrolidone 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 observ~tion and dissolution data showed that the griseofulvin formed by this method was ultrarnicrocrystalline and had a much faster dissolution rate into water at 37 C
than microsized griseofulvin.

..... ....................................................................................................................................................................................
...........

Table 4 1- Spray dried griseofulvin: PVP (~0:30) treated with SLS solution.
2- Spray dried griseofulvin: PVP (70:30).
3- Microsized griseofulvin 4- Spray-dried griseofulvin: PVP treated with the non-ionic polysorbate 80. griseofulvin: PVP: non-ionic (69.7:29.7:0.5)

5- Spray dried griseofulvin: PVP treated with the non-ionic block c~
polymer of ethylene oxide and propylene oxide ~Pluronic~ F77) griseofulvin: PVP: non-ionic (69.7:29.7:0.5)

6- Spray dried griseofulvin: PVP treated with the non-ionic isooctyl phenoxy polyethoxy ethanol. griseofulvin PVP: non-ionic (69.7:29.~:0~5) Sample 1 min. 2 rnin. 3 min. 5 min. 10 min. ,14 min. 15 min.
10.0 10.9 ll.S1~.0 12.5 12.7 2 2.5 3.9 4.9 6.5 9.0 lû.4 --3 1.6 a.7 3.4 4.7 ~.0 ~.2 4 1.9 3.5 4.6 6.3 8.6 ~ 9.7 1.8 3.0 4.0 5.8 B.l -- 9.3 6 1.9 3.1 4.3 6.0 8.6 -- 9.7 Table 5 - Dissolution Profile 1- Spray dried griseofulvin: PVP (70:30) treated with SLS
2- Dorsey Laboratories' Ciris-Peg (Tradern~rk) for griseoful~in composition in PEG 6000.
3- Schering Laboratories' Fulvicin P/G (Trademark1 for griseofulvin composition in PEG 6000.
4- Microsized griseofulvin.

....................... ...................................... .... ...................... ..........

Sample1 min.2 min. 3 min. 5 min.10 min~14 min.
10.0 10.9 11.5 12 012.5 12.7 2 6.9 8.7 ~.7 10.411.3 3 6.û 7.0 7.3 ~.7 8.0 4 1.6 2.7 3.4 417 7.0 8.2 Example 6 In the samples evaluated in Tables 6-8, the following f~rther describes their preparation.

MATERIALS & METHODS

Two grades of hydroxypropyl cellulose were used, Kluce}~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 ~udged by visual microscopic observation under crossed polarizers, or by x-ray diMraction assay.

Preparation of a Melt Mixture 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 w~ter tap, whilerotating 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 chunlcy product was ground to a powder in a micromill.

C stallization with a Sorbitol So}ution r~

Typically, an amount o~ powdered melt mixture w~s 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 sp~tula, 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.

Spray Dried Mixtures .

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 tem perature.

Crystallization with ~5!3~

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 al90 contain ethanol and sorbitol or lactose, but this was found to be UnneCesYary. The doughy mlxture W8S 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 ~

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 frorn becoming pasty. The wetting solution contained 5 mg/ml sodium lauryl sulfate in a rnixture of 4 parts ethanol -1 part water, by volume. The final granular powder contained about 0.2% sodium lauryl sulfate.

..............................................................................................................................................................................................
...

~Z~

Scale-up Attem~ts of Paste Treatment 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 85C. The chunky, partially caked product was milled and screened.

Spray Dried Mixtures of Griseofulvin & Hydro~ellulose ~Klucel) Composition OI Solution Solids Griseofulvin Solvent Content Content Volume (g/l of (% of Ratio Cryst~llinity solvent) Solids) (MeC12/EtOH) of Product 100 50 7/1 Mostly amorphous

7 S 9~1 Amorphous 167 75 8.6/1 Crystalline 200 80 7/1 Crystalline -Table 6 - Dissolution profile.
1- Melt mixture of griseofulvin (75%~Klucel~(25%),crystallized with a sorbitol solution.
2- Micronized griseof ulvin 3- Melt mixture of griseofulvin (83%~Klucel9~17%),amorphous.

lmin. 2 min. 3 min. 5 min. 10 min. 15min. 20 min.
~1.1 8.0 9.2 10.8 12.6 13.4 13.7 2 1.5 2.7 3.4 ~.q 7.0 8.4 9.2 3 0.5 1.0 1.3 2.0 3.2 4.2 5.0 :~21D~

Table 7 _ 1- Spray dried griseofulvin (75%~Klucel~(25%) mixture/ amorphous.
2-Spray dried griseofulvin (50%)-Klucel~ (50%) mixture, mostly amorphous.
3- I!licronized griseofulvin.
4- Spray dried griseofulvin (809$)-Klucel~(20%) mixture crystallineO

SamE~1 min.2 min.3 min.5 min. 10 min.15 min.20 min.
2.0 3.6 4.7 6.5 ~3.8 11.4 12.8 2 2.0 3.6 4.7 6.5 9.2 1~.5 11.8 3 1.5 2.7 3~4 4.7 7.û 8.4 9.2 4 0.8 1.5 2.0 2.8 4.7 5.8 6.5 Table 8 1- Spray dried mlxtur~ o~ griseofulvin: PVP (70:30), treated with SLS
solution.
2- Spray dried mixture of griseofulvin: KlucelD(7$:25), erystallized with sodium lauryl sulfate solution.
3- Micronized griseofulvin Sample 1 min. 2 min. 3 min. 5 min. 10 min.15 min. 20min.
6.2 lLl 11.5 12.0 12.5 12.7 12.8 6.~ 10.2 11.0 11,6 la.l 12~2 12.3 3 1.5 2.7 3.4 4.7 7.0 ~.4 9.2 This example describes preparation of ultramicroerystalline griseofulvin by spray drying a solution of griseofulvin and hydro2~ypropyl 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 ......................................................................................................................................................................... .

6~5 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 H2O was mixed in, and then dried.
Microscopic observation and dissolution data shows that uttramicrocrystalline 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 ultramicrocrystatline griseofulvin by spray drying a solution of griseofulvin and methylcellulose and then treating the powder with a solu-tion of sodium lauryl sulfate. A solution eontaining 4û g of methylcellulose (15 cps) and 12Q 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 partty crystalline by x-ray diffraction. To 4 g of the powder, 4 ml of a 1.5% sodiuml lauryl sulfate solution was added and mixed in. The mixture then was dried. Microscopic observation and dissolution dRta shows that ultramicrocrystatline griseofulvin was formed by this method, and it has a much faster dissolution rate then microsized griseofulvin or untreated material.

~xample 9 This example describes preparation of uttramicrocrystalline griseofutvin by spray drying a solution of griseofutvin and poly (oxypropylene) poly (oxyethylene) block copolymer (Pluronic~F77 BAS~ 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 dri0d 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 uttramicrocrystaltine griseofutvin was formed by this method, and it has a faster dissolution rate then microsized griseofulvin or untreated materiat.

........... ................ . .......................................................................................................... . ....... .... .

Example lO
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 lO0 g of polyethylene glycol 6000 dissolvedinto methylene chloride was spray dried. To 4 g of the powder, 2 ml of a 1.5%
sodium lauryl sulfate solution ~vas 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 materi~l.

ExamE~_ ll This example describes preparation of ultramicrocrystalline griseofulvin by spray drying a solution containing griseofulvin and hyclroxypropyl 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 lO0 ml of ethanol dissolved into 2 liters of methylene chloridewas 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 OI
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.

Example 12 This example describes preparation of ultramicrocrystalline griseofulvin by spray drying A solution of griseof~dvin and polyvinylpyrr~idone 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 added9 mixed and then driedO
Microscopic observation and dissolution data shows that ultramicrocrystalline griseofulvin was formed by this method, and it has a much Paster dissolution rate then microsized griseofulvin or untreated material.

.................................................................... ...................................................................................................................
...

Example 13 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.

Example 14 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 sulfosucoinate. A solutionof 70 g of griseofulvin and 30 g of polyvinylpyrrolidone dissolved into 2 liters of methylene chloride was spray dried Rt 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 rnuchfaster dissolution rate then microsized griseofulvin or untreated material.

Example 15 This example describes preparation of ultramicrocrystalline griseofulvin by spray drying a soluSion 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 th~t ultramicrocrystalline griseofulvin was formed by this method, and it has a much faster dissolution rate then microsized griseofulvin or untreated material.

.................................................................................... ................................................................................

Table g The results of dissolution studies on the samples prepared by Examples 7-15 are listed below. The unit of expression ~or this Table is per cent of saturation achieved in time expressed in minutes.

................................................................................................................................................. .. .. . . . . .

--2~--u7 U7 .t77 27 W u7 ~ne,7 0 W O C7 cn 7 u7 ~ r7 U7 r7 0 c7 ~ O = O ~77 u7 I r. 0 _ o7 Cn _ 07 _ C~7 C~7 C u7 r7 7 r7 .renc~7 ~ r7 7 . = ~ ~r t" c~7 r7 u7 ~_ u7 7 ~. W r~Cb W cncn W c~ c~ r.
C7 u~ I r7 cn r7 r7 W~r O 7 r7 0 37 cn C7 I r~_ ~. W cn cn r.0~cn W o~ o~ cc O
I r~~7 W O c:~ u~ r~c~ 0~ W
_j I o O w cn 0 u7C~ W en ~r u~ ~7 Ct7 r~j !

C' N ¦ N cnc ' O W ~u7 r7 ~`7 O~ O ~ U~ j _ ~ 0 u, d ~~ u' r~ u~ J Ob _~ r~
~ C~ u~ ~_ W0~ r~ r ,8 O I ~0~ cn e~ P ~ r7 r7en 0 W o ~c7 U ¦ OCi 0; cn07 0; 0 e;~r 2- U7 a~ W
.,71 _~r a7 w u~ ~77 ~77 ~c7 t_ t_ u7 o~ ~r ~1 . . . ' , I
U ~ O ~ ~7 ~ u~ u~ o O ~ C~ u7 ~- ' ~- ' ' ' ' ' ' , . . . .
~ ~1 z 0 0 æ0 O _ J O O _ C; O , . ~ ', ' ', ', '.' ' . ' .
U I . '.' ' I
~ '~S I , ~ O~ 7 W t_ 1_ . O~ W ~c7 ~, ,' . . .. .
~C t~ I Z ~r c~ o; cn cn 2~ c~ c~ r" ~
- , .
slu u ~o sl c~C? C~ C~

a~ 1 8 i _ ,~ ,8 ~L0 ~8 ,~ 3 3 ' 3 3 Sl ¦ Z ,~ , ~ 3 ~ o 3 ~ ~ 3 3 3 ~. U U ' C'~ o 0~ C ~20 '8 ~ U c~ Sl C0~ b~
c~ æ æ æ æ ~ U b O C o ~ O ~ C~ U C~ o O L
Z '` ^ C~ ~ ~ C C` = -- = C. ~ ^ C,) 5~ ',"
' ' ~ ''' ' ...... " ................................................................................................ . . . ..

~2~

Example 16 The relative bioavailability of the composition of this invention with two different polymer mixtures and that of one marketed ultramicrosize griseofuivin 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 125mg tablets) to 15 healthy adult volunteers divided into three groups usin~ a crossover experimental design. The total tablet weight for each of the 1~5 mg dosages was 350 mg. The compositions of the invenffon were represented by spray dried griseofulvin mixtures with either polyvinylpyrrolidone or hydroxypropyl cellulose both treated with SLS. The marketed product evaluated was Schering'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-PYP Gris-hydroxypropyl cellulose Marketed Product Free T tal Pree Total Free Total 0-24 hours 48:6 75.8 50.3 81.1 48.9 76.7 24-48 hours 19.1 30.0 20.7 33.3 19.5 37.1 0-48 hours 68.7 105.8 71.0 114.~L 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 mgof micronized griseofulvin. Since ~riseofulvin 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.

~2~)4~i~5 The cumulative mean was as follows:

5~0m~Griseofulvin Tablet 500m~ Griseofulvin as 2x250mg capsules FreeTotal Free Total 0-24 hours 34.435.5 38.0 54.7 24-48 hours 63.5104.2 64.4 102.8 0-48 hours 97.9157.9 102.4 157.5 Example 17 Typical direct compression tablet formulations may be prepared as follows for 125 mg dosage forms having a final tablet weight of 350 rng.

A. 1. Griseoflllvin at 59.5% in mixture with hydroxypropyl cell~ose, SLS treated 210.0 g 2. Microcrystalline Cellulose 87.0 g 3. L~ctose, Edible 32.û g 4. Sodium Starch Glycolate 17.5 g 5. Magnesium Stearate U.S.P. 3.5 g Theoretical Tablet Weight 35D mg.

B. 1. Griseofulvin at 67.5% 18S.0 g in PVP mixture trea~ed with SLS

2. Microcrystalline Cellulose 87.0 g 3. Lactose, Edible 67.0 g 4. Sodium Starch Glycolate 17.5 g .. ................................................................... . .... ... . . .

5. 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 unforrnulated powdere~ material.

....

.. ..... .......... ......................................................................................................................................................
........ ...........

Claims (19)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A pharmaceutical composition in dry solid form comprising a mixture of a therapeutically effective amount of a poorly water soluble or water insoluble drug and a non-toxic, pharmacologically acceptable, water-soluble polymer; said mixture being the product of a melt mix of a dried solution and said mixture in dry solid form having been treated with a solution comprising water and a minor amount of a wetting agent selected from anionic and cationic surfactants and then dried.

2. The composition of claim 1 wherein said polymer is selected from at least one of polyvinyl-pyrrolidone, hydroxypropylrnethyl cellulose, hydroxy-propyl cellulose, methyl cellulose, block co-polymer of ethylene oxide and propylene oxide, and polyethylene glycol.

3. The composition of claim 1 wherein said wetting agent is an anionic surfactant selected from sodium lauryl sulfate, sodium laurate, dioctylsodium sulfosuccinate, sodium stearate, potassium stearate and sodium oleate.

4. The composition of claim 1 wherein said wetting agent is a cationic surfactant selected from benzalkonium chloride and bis-2-hydroxyethyl oleyl amine.

5. The composition of claim 1 or 2 wherein the concentration of said drug is from about 0.1% to about 95% by weight and the concentration of said polymer is from about 5% to about 99% by weight.

6. The composition of claim 1 or 2 wherein the concentration of said drug is from about 50% to about 90%
by weight and the concentration of said polymer is from about 10% to about 50% by weight.

7. The composition of claim 1 or 2 wherein the concentration of said drug is about 50% to about 80% by weight and the concentration of said polymer is from about 20% to about 50% by weight.

8. The composition of claim 1, 2 or 3 wherein the concentration of the wetting agent in the drug-polymer mixture is from about 0.025% to about 2.0% by weight.

9. The composition of claim 1, 2 or 3 wherein the concentration of the wetting agent in the drug-polymer mixture is from about 0.2% to about 1.0% by weight.

10. The composition of claim 1, 2 or 3 wherein said drug is griseofulvin.

11. The composition of claim 1, 2 or 3 wherein said drug is griseofulvin in a concentration ranging from about 0.1% to about 90% by weight; the concentration of the polymer is from about 5% to about 95% by weight, and the concentration of the wetting agent in the drug-polymer mixtures is from about 0.025% to about 2.0% by weight.

12. The composition of claim 1, 2 or 3 wherein said drug is griseofulvin in a concentration ranging from about 50% to about 80% by weight, the concentration of the polymer is from 20% to about 50% by weight, and the concentration of the wetting agent in the drug-polymer mixture is from about 0.02% to about 1.0% by weight.

13. A pharmaceutical composition in solid form comprising a mixture of at least about 0.1% to about 90% by weight of griseofulvin, from about 5% to about 95% by weight of a polymer selected from poly-vinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, block co-polymer of ethylene oxide and propylene oxide, and polyethylene glycol; and from about 0.025% to about 2.0% by weight of a wetting agent selected from anionic surfactants which was added to the drug-polymer mixture in dry solid form by a wet treatment from a solution comprising water; wherein said drug polymer mixture is the product of a melt mix or of a dried solution and said composition was dried following the wet treatment.

14. The composition of claim 13 wherein the concentration of griseofulvin is from about 50% to about 80% by weight, from about 20% to about 50% by weight of a polymer selected from polyvinylpyrrolidone and hydroxypropyl cellulose; and from about 0.2% to about 1.0% by weight of an anionic surfactant selected from sodium lauryl sulfate, sodium sulfate and dioctyl-sodium sulfosuccinate.

15. A compressed pharmaceutical tablet comprising the composition of claim 1, 13 or 14 wherein said drug is in the form of ultramicrocrystals and pharmaceutically acceptable excipients.

16. A method of preparing a pharmaceutical composition with increased bioavailability in mammals from a poorly water soluble or water insoluble drug, which comprises (a) forming a solution of the drug with a pharmacologically acceptable, water soluble polymer, (b) drying the drug-polymer solution, (c) treating the dried drug-polymer solution with a wetting sufficient amount of a solution comprising water and a wetting agent selected from anionic and cationic surfactants, and (d) drying the mixture of step (c).

17. The method of claim 16 wherein said polymer is selected from polyvinylpyrrolidone, hydroxy-propyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyethylene glycol and block co-polymers of ethylene oxide and propylene oxide and said wetting agent is an anionic surfactant selected from sodium lauryl sulfate, sodium laurate and dioctyl sodium sulfo-succinate.

18. The method of claim 16 wherein the solution of the drug and polymer is formed in a mutual solvent, the drug is griseofulvin and wherein the concentration of griseofulvin in the dried mixture of step (d) is from about 0.1% to about 90% by weight and the concentration of the wetting agent in the dried mixture is about 0.025-2.0% by weight.

19. The method of claim 18 wherein the griseofulvin concentration is from about 50% to about 80% and the concentration of said wetting agent is from about 0.2% to about 1.0%.