Note: Descriptions are shown in the official language in which they were submitted.
s
--1--
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
..............................................................................................................................................................................................
..... .
--2--
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
--4--
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;
...... ....................................................................................................................................................................................
............
--5--
(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
--6--
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.
.,
................................................................................................................................................... . . ......
- 9 -
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~
10-
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
-12-
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.
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--13--
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.
....................... ...................................... .... ...................... ..........
-14-
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%
. .,
-1 5-
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~
--16-
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~
--17--
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
-18-
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.
........... ................ . .......................................................................................................... . ....... .... .
-19--
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.
.................................................................... ...................................................................................................................
...
-20-
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.
.................................................................................... ................................................................................
--21--
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
U7 1
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~
-23-
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
-24-
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
.. ................................................................... . .... ... . . .
--25--
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.
....
.. ..... .......... ......................................................................................................................................................
........ ...........
