Increasing the absorption rate of insoluble drugs

The absorption in body fluids of poorly soluble drugs is enhanced by forming a glassy solid matrix of a carrier and the drug. A solution of the drug and the carrier is formed at an elevated temperature either with or without a solvent and chilled rapidly to form a solid mass which can be ground to a powder for oral administration in a tablet or capsule.

This invention relates to the absorption of drugs. More particularly, it 
relates to increasing the absorbability of insoluble or relatively 
insoluble drugs in aqueous gastric fluids. 
The poor solubility of some drugs in aqueous gastric fluids leads to 
erratic and incomplete absorption in the gastrointestinal tract. It is 
known that a reduction in particle size, e.g., micronization, will enhance 
solubility and increase absorption; however, the results have not been 
completely satisfactory as there is a tendency for the fine sized drug 
particles to agglomerate, thus decreasing their solubility. 
The prior art has also taught the preparation of eutectic mixtures and 
solid solutions of relatively insoluble drugs with a pharmacologically 
inert, readily soluble carrier. For example, British Pat. No. 942,743 
discloses the preparation of a solid solution of an estrogen and a carrier 
for use as a pessary. The solid solution is prepared by cooling a molten 
solution of the estrogen and carrier which is then powdered and 
incorporated into pessaries. However, the reference only provides estrogen 
pessary compositions which precipitates the drug without contemplating 
increasing the absorption thereof in an aqueous medium. 
It is, therefore, an object of this invention to provide a composition and 
method for increasing the absorbability of insoluble or relatively 
insoluble drugs in aqueous gastric fluids of animals, e.g., higher 
primates, without the disadvantages of the prior art. 
This invention provides for a novel method of increasing the absorption in 
aqueous gastric fluids of insoluble or relatively insoluble drugs by 
treating a living body with an insoluble or relatively insoluble drug that 
has been incorporated in a solid solution, e.g., a glass like solid of a 
carrier. 
This invention provides two methods for preparing the solid solutions of 
drug and carrier, both methods yield the same product. In accordance with 
one method, the desired drug and the carrier are heated together until the 
drug is dissolved in the carrier. In accordance with the second method, a 
volatile, mutual solvent is employed with heating to prepare a solution of 
the drug in the carrier. The exact temperature required to bring the 
mixture of the drug and the carrier or the mixture of the drug, carrier 
and the solvent into solution will vary. It is dependent on the solubility 
and the concentration of the drug, the carrier used, and the nature and 
the amount of the solvent used. The volatile solvent may be removed by 
heat and/or vacuum. Either method produces a heated solution of the drug 
in the carrier. This heated solution is then chilled rapidly to form a 
solid solution which is then reduced in particle size, for use in the 
preparation of tablets or capsules. 
The carriers which may be utilized in the present invention are 
polyethylene glycol polymers, pentraerythritol, pentaerythrityl 
tetraacetate or citric acid (e.g., monohydrous citric acid). 
The preferred carrier utilized in the present invention is a polyethylene 
glycol polyer (PEG) which is solid at room temperature. Such solid 
polymers have a molecular weight of from 1,000 to 20,000 or higher and the 
polymers having an average molecular weight of from about 4,000 to 6,000 
are preferred for purposes of the present invention. Suitable polymers are 
available commercially under the trademark CARBOWAX, Union Carbide 
Corporation. 
This invention is applicable to any drug insoluble or relatively insoluble 
in body fluids which is soluble in the carrier or co-solvent utilized. 
The invention is particularly useful in increasing the absorbability of 
drugs such as griseofulvin (gris), levo dopa, d-propoxyphene, meperidine, 
methadone, erthromycin, ampicillin, prednisone, prednisolone, 
benzodiazepines (e.g., temazepam, chordiazepoxide, and the like), codeine, 
methaqualone, steroidal estrogens, noscopien, digoxin, digitoxin, 
testosterone, methyl testosterone, oral contraceptives, hexobarbital, 
organic nitrates, such as pentaerythritol tetranitrate, and the like. Due 
to the nature of the organic nitrates, the solvent method but without the 
use of heat, is preferred for the preparation of these drug-carrier 
compositions. 
In preparing the formulations of the present invention, a drug (e.g., 
griseofulvin) is first incorporated in the carrier (e.g., PEG) as a 
solution at a temperature of about 100.degree. C. In the case of many 
drugs, this temperature can be exceeded in order to place the drug in 
solution and no mutual solvent is necessary. Thus if the drug is heat 
stable, the drug and the carrier are combined in the desired 
concentrations and heated to the temperature necessary to bring them into 
solution. If desired, a mutual solvent can be used such as 
N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, butanol, 
ethanol, chloroform, and the like. The solvent is necessary if the drug 
will not otherwise go into solution at a temperature below its 
decomposition point. After the drug is in solution, the mixture is cooled 
to about 100.degree. C. or other appropriate temperature depending on the 
nature of the drug and its concentration and the solvent is removed, using 
reduced pressure if necessary, to produce a melted solution of the drug in 
liquid carrier. It is not always necessary to remove the solvent 
completely but this should, of course, be done if the solvent is toxic. At 
this time the homogenous liquid may be shock cooled by passing it over a 
chilled roller or a metallic heat exchange system so that the mass is 
cooled in about a period of a few minutes to about room temperature (e.g., 
10.degree. C. to 30.degree. C.). The plastic mass resulting from the 
cooling is now allowd to sit at about room temperature until the mass 
hardens. The time required for hardening, ranging from a few minutes to a 
few days, will depend on the nature of the drug and its concentration and 
the carrier used. For example, a preparation containing 2% of griseofulvin 
in PEG 6,000 requires less than one hour to harden. The mass can now be 
made up into tablets or capsules using conventional techniques. 
Alternatively, the homogeneous liquid described above may be shock cooled 
by atomization into an inert liquid in which the drug and PEG are 
non-soluble, and which is maintained at a low temperature, e.g., 
-60.degree. C. to 30.degree. C. The homogenous liquid is thus instantly 
cooled and particulated, and may be removed from the inert liquid, by 
conventional methods, such as filtration. For example, the homogeneous 
liquid may be injected into dry ice cooled heptane bath by means of an 
atomizer, e.g., needle, immersed in the heptane. The homogeneous liquid is 
instantly cooled and particulated in the heptane. 
The particle size of PEG-drug composition prepared by this method may be 
controlled by the fineness of the atomization, and compositions thus 
prepared may be suitable for direct formulation into tablets or capsules 
using conventional techniques. 
From 2 to 50% by weight of the desired drug can be incorporated in the 
carrier utilizing the above techniques. Naturally, the solvent will be 
employed in the case of those drugs which are heat labile while either 
simple melting or solvent can be used with heat stable drugs. 
The following non-limiting Examples I to IX illustrate methods of making 
the preparations of the present invention. Examples X and XI are a 
dissolution rate study of drug-carrier compositions of this invention.

EXAMPLE I 
A 10 gram mixture of 10% by weight of gris and 90% by weight of PEG 4,000 
(number refer to average molecular weight of polyethylene glycol polymer) 
was prepared. The mixture was heated with a constant stirring on a hot 
plate until it was melted. This required a time of about 5 minutes and the 
maximum temperature was 180.degree. C. The melt was then poured onto a 
stainless steel plate which was cooled by a stream of cold air or water 
(preferred temperature 0 to 25.degree. C.) flowing on the opposite side of 
the plate. The mixture was thus cooled in a matter of a few minutes to 
substantially room temperature but at this point the mass was soft and not 
easily subdivided. The mixture was stored in a desicator at room 
temperature and after 48 hours, it was brittle and could be easily 
pulverized. The solid mass was then pulverized in a mortar or a ball mill 
and the powder was sieved to 80 to 200 mesh range. The powder could then 
be incorporated in tablets or capsules. 
EXAMPLE II 
The procedure similar to Example I was carried out (the maximum temperature 
used was higher for the higher concentration of the gris). PEG 6,000 was 
empolyed and the concentration of gris was 25%. 
EXAMPLE III 
The similar procedure of Example I was again carried out but this time PEG 
20,000 was employed and the concentration of gris was 50%. 
EXAMPLE IV 
A mixture of 0.5 grams gris and 4.5 grams of PEG 6,000 was suspended in 500 
ml. of absolute alcohol in a beaker and concentrated directly on a hot 
plate to about 100 ml. The resulting cloudy suspension was further 
concentrated on an oil bath, kept at 115.degree. C. for one hour when the 
formation of ethanol vapor bubbles was no longer observed. The hot mixture 
was spread on a cool metal surface and cooled to room temperature rapidly. 
The sample was powdered and the 80 to 200 mesh fraction was collected. 
EXAMPLE V 
The similar procedure of Example IV was repeated except that a 20% gris 
mixture was prepared utilizing 1 gram of gris and 4 grams of PEG 6,000. 
EXAMPLE VI 
A mixture was made containing 5% hydrocortisone acetate and 95% PEG 6,000. 
The mixture was heated on a hot plate until dissolution was achieved and 
the material was then cooled rapidly as was described in Example I. 
EXAMPLE VII 
A mixture was prepared containing 5% of prednisolone acetate and 95% by 
weight PEG 6,000. This was processed in accordance with the procedure of 
Example I. 
EXAMPLE VIII 
A mixture was made containing 5% 17-methyltestosterene and 95% by weight of 
PEG 6,000. This was processed into a powder in accordance with the 
technique of Example I. 
EXAMPLE IX 
A mixture was made containing 2% digitoxin and 95% PEG 6,000. This was 
processed into a powder in accordance with the technique of Example I. 
EXAMPLE X 
Drug dissolution rate-studies were conducted to demonstrate the increase in 
the absorption rate of drugs following the teachings of this invention. 
The compositions of Table I were prepared as described in Example I. The 
studies were conducted as follows: 
A recycling and automatic recording system was used for all dissolution 
rate studies. The dissolution rate of gris in different physical forms 
were run in 500 ml. distilled water in a 600 ml. beaker at room 
temperature. 
Unless otherwise specified, samples of 80 to 200 mesh powder were 
transferred directly into the dissolution medium and stirred with a 
stainless steel paddle. The paddle, 5.5 .times. 2.7 cm., was placed at the 
center of a 500 ml. dissolution medium and rotated at a rate of 100 r.p.m. 
The solution was pumped by a peristatic pump (Multi-speed Transmission, 
model No. 6000-000, available from the Harvard Apparatus Co., Dover, 
Mass.) at a rate of 80 to 100 ml./min. through a glass filter stick to a 
1-cm. flow cell and then back to the dissolution apparatus. The absorbance 
of the solution is monitored by a recording Beckman DB spectrophotometer 
at either the miximum peak of gris, 292 mu., or minimum absorbance, 272 
mu. depending upon the concentration of gris. In the system of gris-PEG 
20,000, 324 mu. was used because of possible interference of absorption by 
the polymer at 272 mu. The volume of the solution in the tubing of the 
recycling system is about 10 ml. At the flow rate used, the monitored 
absorbance will reach 90% of the equilibrium valve in 15 sec. Therefore, 
the lag time in the measurement of dissolution rate is essentially 
negligible. In the study of the dissolution rate at room temperature, the 
water is preadjusted to 25.degree. C. The ambient temperature of the room 
ranged less than 2.degree. from this temperature. 
The solubility of gris at 25.degree. C. is 1 mg/100 ml. of water, the 
amount of gris in the various solid dispersion systems used for the 
dissolution rate study in 500 ml. water was usually 5 mg., which would 
saturate this volume of the solvent. 
Samples of micronized gris and of gris of 100 to 200 mesh particle size 
distribution were also run. They were prepared by rapidly melting and 
cooling gris and then pulverizing and sieving to 100 to 200 mesh or 
micronizing. All samples were run in duplicate. 
The results are shown in Table I. 
Table I 
______________________________________ 
Twenty, Fifty, and Seventy Percent Dissolution 
Times for Various Griseofulvin Compositions in 
Saturation Dissolultion Apparatus.sup.a 
20% 50% 70% 
gris compositions min. min. min. 
______________________________________ 
100-200 Mesh pure gris 
60.0 -- -- 
Micronizied gris (nonwetted) 
25.0 -- -- 
Micronized gris (wetted) 
2.0 30.0-0.0 -- 
5% gris-PEG 6000 1.0 0.3 1.5 
10% gris-PEG 6000 1.0 0.5 3.0 
20% gris-PEG 6000 1.0 3.0 15.0 
40% gris-PEG 6000 1.0 14.0 -- 
5% gris-PEG 4000 1.0 0.3 2.0 
5% gris-PEG 20,000 
1.0 0.6 2.5 
20% gris-PEG 20,000 
1.0 4.0 -- 
7.5% gris-pentaerythritol 
1.0 0.5 4.0 
20% gris-pentaerythritol 
1.0 3.8 15.0 
10% gris-Pentaerythrityl 
1.0 8.0 -- 
tetraacetate 
10% gris-succinic acid 
1.2 10.0 50.0 
5% gris-citric acid 
1.0 0.2.sup.b 
0.3.sup.b 
20% gris-citric acid 
1.0 1.0 5.0 
______________________________________ 
.sup.a Five milligrams gris in 500 ml. of water at 25.degree.. 
.sup.b Dissolution times taken from recorded absorbance readings. Values 
are not corrected for the circulation lag time of approximately 15 
seconds. 
Table I compares the studies utilizing the time it took for each 
preparation to reach 20% dissolution, 50% dissolution and 70% dissolution. 
The dissolution rate of the nonwetted, micronized gris is markedly slower 
than that of the same powder when wetted first prior to study (with 2 ml. 
of 0.2% polysorbate (Tween 20 ) solution). Furthermore, the unwetted 
sample has almost the same dissolution rate as the 100-200 mish gris, thus 
indicating the serious agglomeration problem inherent with water-insoluble 
drugs, such as gris. 
The strikingly fast dissolution rates of gris dispersed in various carrier 
systems are shown by this study. Even the preparation containing 40% of 
gris in the system of gris-PEG 6,000 (designated by 40% gris-PEG 6,000) 
possesses faster dissolution rate than the wetted micronized gris. This 
rapid dissolution may be attributed by the molecular and/or colloidal 
dispersion of gris in the carrier matrix. Owing to the similar physical 
and chemical properties of PEG 4,000, 6,000, and 20,000, it is 
understandable that gris dispersed in these three carriers all exhibit 
approximately the same dissolution characteristics. 
A number of tests were made to establish that the gris was not decomposed 
in any manner following either the solvent or the direct fusion methods of 
preparing the solid solutions. The melting point, the spectra of the 
ultra-violet, the infrared and fluorescence are all identical to those of 
the gris used as a starting material. Thin layer chromatography was 
employed and no additional spots were detected on the material which had 
been formed into the solid solution. 
Dissolution studies were similarly made involving other materials. In the 
case of pure prednisolone acetate it was found to require 8 minutes to 
achieve a 20% dissolution in water while a preparation made in accordance 
with Example VII required considerably less than 1 minute. In the case of 
pure methyltestosterone, the time for 20% dissolutiom was 2 minutes while 
the PEG solid solution required less than 1 minute. In the case of 
hydrocortisone acetate, more than 20 minutes were required for the pure 
material and considerably less than 1 minute for the solid solution with 
PEG 6,000. 
In the case of the microcrystalline digitoxin, about 15 minutes were 
required while the solid solution with PEG 6,000 required less than 1 
minute. 
A series of experiments were made employing dogs, wherein oral preparations 
were fed to the dogs and blood samples withdrawn at intervals after 
feeding and the plasma analyzed for known metabolites of gris. In this 
series of experiments, it was found that the concentration of gris rose 
much more rapidly in the case of the solid solution of the present 
invention when compared with commercial micronized tablet and capsule 
preparations. 
In order to establish that it was the physical form of the gris and not the 
mere presence of the PEG which contributed to the rapid rise, a comparison 
was made between 5% gris prepared as a solid solution in PEG 4,000 in 
accordance with the technique of the present invention and a similar 
preparation wherein 5% micronized gris was merely suspended in PEG 4,000. 
The results of these tests are shown in FIG. 1. It will be seen from FIG. 
1 that the plasma concentration at about 100 minutes was only about 0.1 
mcg. per ml. in the case of the gris which was merely suspended in PEG 
4,000, while it averaged about 10 times this amount when fed as a solid 
solution prepared in accordance with the technique of the present 
invention. 
In addition to drug, other materials which may or may not be biologically 
active may be incorporated in the PEG-drug system within the scope of this 
invention. 
EXAMPLE XI 
Bioavailability of Griseofulvin from GRIS-PEG 
Using the GRIS-PEG formulations of this invention, the following two tests 
were run to determine the bioavailability (absorption) of griseofulvin. 
Test #1 
Thirty-six male volunteers were randomly assigned to three groups of equal 
size by means of a table of random numbers. 
Group A (12 subjects) received a single, oral dose of 500 mg. of a 
commercially available formulation (tablet) of micronized griseofulvin. 
Group B (12 subjects) received two 125 mg. GRIS-PEG tablets (griseofulvin 
in a PEG-6,000 formulation, prepared as described in Example I). Group C 
(12 subjects) received four of the 125 mg. GRIS-PEG tablets. All subjects 
received the tablets at 8:00 a.m. with 4-6 ounces of water. Blood samples 
for the determination of the concentration of griseofulvin in plasma were 
obtained at zero time and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours 
after the oral administration of the test medications. 
Test #2 
Twelve normal, healthy males participated in a doublebline, single dose 
crossover test. Group I received a single, oral dose of 500 mg. of a 
commercially available micronized formulation (tablet) with 4-6 ounces of 
water on Test Day 1. Group II received a single, oral dose of 250 mg. of 
the GRIS-PEG tablets of this invention with 4-6 ounces of water on Test 
Day 1. Assignment of subjects to a treatment group was based on a table of 
random numbers. 
On Test Day 9, following a washout period, which extended from Test Day 3 
to Test Day 8, the subjects were crossed over and received the second test 
medication. 
Blood samples for the determination of the concentration of griseofulvin in 
the plasma were obtained at zero time and at 0.5, 1, 2, 4, 6, 8, 10, 12, 
24, 36, 48, and 72 hours after the oral administration of the test 
medications. 
The following variables were controlled in both Test #1 and Test #2. 
All subjects were between the ages of 21 and 50 years, weighed between 140 
and 200 pounds and were within .+-. 15% of the normal body weight for 
their frame and stature. Additional criteria for entrance into the tests 
included a normal routine physical examination, complete blood count, 
urinalysis and automated serum chemistries. 
All subjects were totally free of significant clinical illness in the two 
weeks preceding the tests, had no surgical or medical condition which 
might interfere with the absorption, metabolism, or excretion of the study 
medications were not taking any other medication. 
During the pretreatment phase (control period), the following parameters 
were studied in each subject; A 12-lead ECG, a battery of hematology 
tests, including a determination of the hemoglobin, hematocrit, and WBC 
count. Blood chemistries included a determination of the following: 
calcium, inorganic phosphorus, fasting blood sugar, BUN, serum uric acid, 
total protein, albumin, cholesterol, total bilirubin, alkaline 
phosphatase, LDH, and SGOT. 
Subjects with abnormal values or findings were not admitted into the tests. 
These parameters were evaluated again on Test Day 2 in Test #1. They were 
also evaluated again in Test #2 on Test Day 2, at the end of the washout 
period, which was Test Day 8 and on Test Day 10. 
No concurent medication was permitted during the course of either Test #1 
or #2. 
Each subject fasted overnight but was allowed water ad lib. No food or 
liquids were allowed until four hours after the ingestion of the test 
medications. 
A gas chromatographic method was employed to determine the concentration of 
griseofulvin in the plasma samples. The gas chromatographic method was an 
adaptation of the method reported by Shah, Riegelman, and Epstein .sup.1 
for the analysis of griseofulvin in skin samples. 
FNT .sup.1 Shah, V.P.; Riegelman, S.; Epstein, W.L.: Determination of 
Griseofulvin in Skin, Plasma and Sweat, J. Pharm. Sci. 61: 634-636, 1972. 
The following quantitative method was employed to determine the 
concentration of griseofulvin in plasma: A 2.0 ml sample of plasma was 
pipetted into a stoppered test tube; 2.0 ml of a saturated sodium chloride 
solution was added, followed by the addition of 10 ml of anhydrous ethyl 
ether. The tube was shaken for one minute. A 5 ml aliquot was then 
transferred to a pearshaped flask and the ether distilled off in vacuo. 
The residue was dissolved in 1.0 ml of glass distilled benzene containing 
1.0 .mu.g/ml of diazepam. A 5 .mu.l aliquot of this solution was injected 
into the gas chromatograph. 
The conditions of analysis were as follows: 
______________________________________ 
Column: 3% OV 17 on Chromosorb W - 5 ft. 
Temperatures: Column - 027.degree. C. 
Injection Port - 310.degree. C. 
Electron Capture - 330.degree. C. 
Carrier Gas: 10% methane - 90% argon 
Flow: 150 ml/min 
Range: 10 
Attenuation: 16X 
______________________________________ 
Standard solutions of griseofulvin were made in benzene in the range of 0.1 
to 2.0 .mu.g/ml. Each standard solution also contained 1.00 .mu.g/ml of 
diazepam as an internal standard. Five .mu.l of each standard solution was 
injected under the same analysis condition as described above. Diazepam 
was found to have a retention time of .about.3 minutes while griseofulvin 
appeared in .about.8 minutes. 
The peak heights ratio diazepam:griseofulvin was plotted against the 
concentration of griseofulvin. The curve was linear between concentrations 
of 0.1 to 1.5 .mu.g/ml. The sensitivity of the method was 0.1 .mu.g/ml. 
The response below 0.1 .mu.g/ml was found to be too small compared to the 
internal standard. Recovery of griseofulvin added to human plasma varied 
from 96-118% with an average value of 103%. The standard deviations were 
approximately 10% for all concentrations employed. The gas chromatographic 
method especially with the electron capture detector was considered to be 
specific for griseofulvin. 
RESULTS 
Test #1--Parallel Group Design 
A single, oral dose of 250 mg. of GRIS-PEG produced essentially the same 
peak plasma concentration, the same time to reach peak concentration, and 
the same area under the plasma level curve as was achieved with a single, 
oral dose of 500 mg. of the micronized formulation of griseofulvin (see 
FIG. 2). 
Following the oral administration of a single 500 mg. dose of GRIS-PEG, the 
peak plasma level and the area under the plasma level curve were 
significantly enhanced when compared to the results achieved with a 500 
mg. dose of a commercially available micronized formulation of 
griseofulvin (see FIG. 2). 
Test #1A--Crossover Design 
In this crossover study, an oral dose of 250 mg. of GRIS-PEG produced 
essentially the same peak concentration and the same area under the plasma 
level as was achieved with a single, oral dose of 500 mg. of a 
commercially available micronized formulation of griseofulvin (see FIG. 
3). 
In Tests #1 and #2, no adverse effects attributable to the study 
medications were observed in the following parameters: vital signs, ECG, 
hematology parameters, blood chemistry parameters, and the urinalysis 
tests. No adverse reactions were reported during the course of these two 
tests. 
The results of the above two tests show that the oral absorption of 
griseofulvin is unexpectedly and unobviously enhanced by the GRIS-PEG 
formulation of this invention and that the same plasma levels were 
achieved with 250 mg. of GRIS-PEG as were achieved with a 500 mg. oral 
dose of a commercial micronized formulation of griseofulvin.