Pharmaceutical compositions containing polyalkylene block copolymers which gel at physiological temperature

There is disclosed a pharmaceutical composition which gels at physiological temperature. The composition is comprised of a block copolymer containing one or more polyoxyethylene blocks and one or more polyoxy (higher alkylene) blocks wherein at least some of the blocks are linked together by a linking group characterised in that the linking group is an oxymethylene group, and a therapeutic agent. The therapeutic agent is present as (i) nanoparticles of the therapeutic agent having the block copolymer adsorbed on the surface thereof, (ii) a suspension in a solution of the block copolymer, or (iii) as an aqueous solution in a solution of the block copolymer.

FIELD OF THE INVENTION 
The present invention is directed to pharmaceutical compositions containing 
a therapeutic agent and a polyalkylene block copolymer which gels at 
physiological temperature. 
BACKGROUND OF INVENTION 
Bioavailability is the degree to which a therapeutic agent becomes 
available to the target tissue after administration. 
Many factors can affect bioavailability including the dosage form and 
various properties, e.g., dissolution rate of the therapeutic agent, 
amount of time the therapeutic agent is exposed to the desired site. 
Therapeutic agents, ranging from poorly to highly soluble in water, can be 
administered more effectively if the therapeutic agent is able to be 
delivered and maintained at the site where its therapeutic effect is 
desired. 
U.S. Pat. No. 4,534,959, there is described a composition in an aerosol 
container. When sprayed the composition gels on the surface of living 
tissue. This composition contains a polyoxyethylene-polyoxypropylene 
copolymer. However the copolymer must be present in high percentage. 
Further, the therapeutic agent must be solubilized. U.S. Pat. No. 
3,867,533 relates to another aqueous gel composition; U.S. Pat. No. 
4,465,663 is similar and relates to cosmetic gels. 
SUMMARY OF THE INVENTION 
In accordance with the present invention there is provided a pharmaceutical 
composition which gels at physiological temperatures and which is 
comprised of 
a) block copolymer containing one or more polyoxyethylene blocks and one or 
more polyoxy(higher alkylene) blocks wherein at least some of the blocks 
are linked together by a linking group characterized in that the linking 
group is an oxymethylene group, and 
b) a therapeutic agent, wherein the therapeutic agent is present as 
(I) nanoparticles of the therapeutic agent having the block copolymer 
adsorbed on the surface thereof, 
(II) a suspension in a solution of the block copolymer, or 
(III) as an aqueous solution in a solution of the block copolymer.

DESCRIPTION OF PREFERRED EMBODIMENTS 
The Block Copolymer--The Gelling Agent 
The block copolymer contains one or more polyoxyethylene blocks and one or 
more polyoxy (higher alkylene) blocks wherein at least some of the blocks 
are linked together by a linking group characterized in that the linking 
group is an oxymethylene group. 
Preferred copolymers of the invention include those wherein the polyoxy 
(higher alkylene) blocks are selected from polyoxypropylene and 
polyoxybutylene blocks. 
In one embodiment, block copolymers are provided having the following 
repeating units in random order 
EQU --(P.sub.n !CH.sub.2 O--).sub.x (E.sub.m !CH.sub.2 O)y-- 
wherein 
P is oxypropylene; 
E is oxyethylene; 
n is an integer from 2 to 70, preferably from 4 to 20; 
m is an integer from 2 to 250, preferably from 9 to 20; 
x is an integer from 1 to 100, preferably from 1 to 10; and, 
y is an integer from 1 to 100, preferably from 1 to 50. 
In a preferred embodiment block copolymers are used having the following 
repeating units in random order: 
EQU --(E.sub.r P.sub.s E.sub.r)CH.sub.2 O!.sub.z -- 
wherein 
P is oxypropylene; 
E is oxyethylene; 
r is an integer from 2 to 160, preferably from 75 to 150; 
s is an integer from 15 to 65, preferably from 30 to 50; and, 
z is an integer from 2 to 50, preferably from 2 to 10. 
In a particularly preferred embodiment block copolymers are used having the 
following repeating units in random order: 
EQU -(E.sub.r P.sub.s E.sub.r)CH.sub.2 O!.sub.z --(E.sub.t)CH.sub.2 O!.sub.w 
wherein 
P is oxypropylene; 
E is oxyethylene; 
r is an integer from 2 to 160, preferably from 75 to 150, most preferably 
141; 
s is an integer from 15 to 65, preferably from 30 to 50, most preferably 
44; 
z is an integer from 2 to 50, preferably from 2 to 10, most preferably 4 to 
8; 
t is an integer from 1 to 10, preferably from 1 to 3, most preferably 1; 
and 
w is an integer from 2 to 50, preferably from 2 to 10, most preferably 4 to 
8. 
The molecular weight of a block copolymer as measured by gel permeation 
chromatography against poly(oxyethylene) standards may range from 10,000 
to 500,000, preferably from 50,000 to 250,000. 
The polymers can be prepared by a process wherein one or more dihydroxy 
terminated polymers selected from poly (ethylene glycol), poly (higher 
alkylene glycol) and block copolymers thereof are reacted in solution with 
a dihalomethane in the presence of a base. 
Examples of suitable solvents in which the reagents can be dissolved 
include dihalomethanes and other known organic solvents such as benzene, 
chlorobenzene and toluene or mixtures thereof. 
Preferably, an excess of the dihalomethane reagent is used as the solvent. 
Even though the dihalomethane is used in an amount which can far exceed 
the stoichiometric amount needed to couple with the polymeric reactants, 
products of high molecular weight can still be achieved. 
Although any dihalomethane or mixture thereof may be used such as 
dichloromethane, dibromomethane or diiodomethane, the preferred 
dihalomethane is dichloromethane. 
The required alkaline reaction conditions may be obtained by incorporating 
one or more bases such as sodium hydroxide and potassium hydroxide. 
Examples of the dihydroxy terminated polymer starting materials include the 
polyethylene glycols (PEGs) and the polypropylene glycols (PPGs) which are 
available commercially. Specific examples include PEG 400, PEG 6000 and 
PPG 1000 for which the number associated with the name "PEG" or "PPG" 
indicates the average molecular weight of the polymer and is proportional 
to the average number of repeating oxyethylene or oxypropylene units in 
the polymer. Preferred polyalkylene glycols have molecular weights ranging 
from 200 to 10,000 and particularly PEG 6000. 
Further examples of the dihydroxy terminated polymer starting materials 
include the dihydroxy terminated E--P--E triblock copolymers of 
poly(oxyethylene) (E) and poly(oxypropylene) (P) which are commercially 
available in the form of Pluronic.TM. surfactants. These starting 
materials provide the "(E.sub.r P.sub.s E.sub.r)" portion of the block 
copolymers defined above. Preferred triblock copolymers have molecular 
weights ranging from 4,000 to 15,000. Particular Pluoronic.TM. surfactants 
that can be used as starting materials include F108, F68, F127 and L6000 
and particularly-F108. Triblock copolymers derived from F108, which has 
longer chain lengths of propyleneoxy groups, provide better hydrophobic 
interactions with the therapeutic or diagnostic agent particles. This 
provides better size reduction of particles. Further, F108 has a gel point 
very close to physiological temperature at low concentrations. F108 
corresponds to the "(E.sub.r P.sub.s E.sub.r)" portion r is 141 and s is 
44. 
The copolymers contain both hydrophilic polyoxyethylene blocks and 
hydrophobic polyoxy (higher alkylene) blocks. The balance between the 
hydrophilicity and hydrophobicity of the copolymers can be adjusted by 
appropriate choice of starting materials to give the optimum physical and 
chemical characteristics required. 
The currently preferred block copolymer has the formula: 
##STR1## 
wherein r is 141; s is 44 and z is 3 to 4. 
The block copolymers that are useful in the present invention have 
desirable rehological properties for use in therapeutic and diagnostic 
compositions. At concentrations as low as 2.5% w/v in phosphate balance 
salt solution (PBS) or in water, particular examples of the described 
block copolymers have gel points close to physiological temperature 
(37.4.degree. C.). The viscosity of these block copolymers at 3.5% and 
5.5% in PBS change abruptly from less than 20 cps at room temperature to 
more than 1500 cps at physiological temperature while the pH and 
osmolality of the block copolymer solutions remain comparable to PBS. 
Thus, compositions containing these block copolymers can be administered 
(e.g. subcutaniously or orally) as low viscosity compositions at room 
temperature and, when they reach physiological temperature, will tend to 
gel. 
Because of these and other properties, the described block copolymers are 
useful as bioadhesives and/or control release agents for the delivery of 
therapeutic or diagnostic agents to the eye, ear, pulmonary systems, 
biocavity and gastrointestinal tract. 
Therapeutic or Diagnostic Agents 
Suitable therapeutic or diagnostic agents useful in the three types of 
formulations used in the present invention (i.e., nanoparticles, solutions 
and suspensions) be selected from a variety of known classes of 
therapeutic or diagnostic agents including, for example, analgesics, 
anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, 
antibiotics (including penicillins), anticoagulants, antidepressants, 
antidiabetic agents, antiepileptics, antihistamines, antihypertensive 
agents, antimuscarinic agents, antimycobacterial agents, antineoplastic 
agents, immunosuppressants, antithyroid agents, antiviral agents, 
anxiolytic sedatives (hypnotics and neuroleptics), astringents, 
beta-adrenoceptor blocking agents, blood products and substitutes, cardiac 
inotropic agents, contrast media, corticosteroids, cough suppressants 
(expectorants and mucolytics), diagnostic agents, diagnostic imaging 
agents, diuretics, dopaminergics (antiparkinsonian agents), haemostatics, 
immuriological agents, lipid regulating agents, muscle relaxants, 
parasympathomimetics, parathyroid calcitonin and biphosphonates, 
prostaglandins, radio- pharmaceuticals, sex hormones (including steroids), 
anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid 
agents, vasodilators and xanthines. Preferred therapeutic or diagnostic 
agents include those intended for oral administration, topically, ophalmic 
and nasal application. A description of these classes of therapeutic 
agents and diagnostic agents and a listing of species within each class 
can be found in Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, 
The Pharmaceutical Press, London, 1989. The therapeutic or diagnostic 
agents are commercially available and/or can be prepared by techniques 
known in the art. 
Solutions and Suspensions 
The pharmaceutical compositions of the present invention can be applied to 
known drugs in nasal, oral and ophthalmic solutions and suspensions to 
produce an increase in sustained drug release, increase in drug residence 
time or to enhanced bioavailability. 
The present block copolymers are particularly useful with therapeutic 
agents for the treatment of the eyes such as the following: 
A. for ophthalmic solution application--acetylcholine chloride, atropine 
sulfate, benoxinate hydrochloride, carbachol, chloramphenicol, 
chymotrypsin, cromolyn sodium, cyclopentolate hydrochloride, demecarium 
bromide, dexamethasone sodium phosphate, neomycin sulfate, dipivefrin 
hydrochloride, echolthiophate iodide, epinephrine, epinephrine bitartrate, 
epinephryl borate, eucatropine hydrochloride, flurbiprofen sodium, 
gentamicin sulfate, glycerin, gramicidin, polymyxin B sulfates, 
homatropine hydrobromide, hydroxyamphetamine hydrobromide, hydroxypropyl 
methylcellulose, hydrocorticone, idoxuridine, levobunolol hydrochloride, 
naphazoline hydrochloride, neomycin, gramicidin, oxymetazoline 
hydrochloride, phenylephrine hydrochloride, phystigmine salicylate, 
pilocarpine hydrochloride, pilocarpine nitrate, prednisolone sodium 
phosphate, proparacaine hydrochloride, scopolamine hydrobromide, 
sulfacetamide sodium, sulfisoxazole diolamine, tetracaine hydrochloride, 
tetrahydrozoline hydrochloride, timolol maleate, tobramycin, tropicamide 
and any of their combinations. 
B. for ophthalmic suspension application--chloramphenicol, dexamethaxone, 
neomycin, fluorometholone, hydrocortisone acetate, hydrocortisone, 
medrysone, natamycin, prenisolone acetate, oxyteracycline hydrochloride, 
polymyxin B, sulfacetamide sodium, tetracycline hydrochloride and any of 
their combinations 
The present block copolymers are also particularly useful with therapeutic 
agents for the nasal application such as the following: cromolyn sodium, 
cyclopentamine hydrochloride, ephedrine sulfate, ephinephrine, 
flunisolide, lypressin, naphazoline hydrochloride, oxymetazoline 
hydrochloride, oxytocin, phyenylephrine hydrochloride, tetrahydrozoline 
hydrochloride and xylometazoline. 
The present block copolymers are also particularly useful with therapeutic 
agents in solutions and suspensions for oral application such as the 
following: A- oral solutions--acetaminophen, aminobenzoate, aminophylline, 
amprolium, aspirin, carphenzaine maleate, chloramphenicol, clindamycin 
palmirate hydrochloride, cloxacillin sodium, cloxacillin sodium, 
cyanocobalamin Co, cyclosprine, dihydrotachysterol, diphenoxylate 
hydrochloride, atropine sulfate, doxepine hydrochloride, ergocalciferol, 
ergoloid mesylates, fluphenzaine hydrochloride, glycerin, guaifenesin, 
theophyline, haloperidol, hyoscyamine sulfate, isosorbide, levocarnitine, 
mesoridazine besylate, methadone hydrochloride, methenamine mandelate, 
metoclopramide, nafcillin sodium, neomycin sulfate, nortriptyline 
hydrochloride, oxacillin sodium, oxycocone hydrochloride, paramethadione, 
penicillin G potassium, perphenazine, prednisone, prochlorperazine 
edisulate, promazine hydrochloride, theophylline, guaifenesin, 
thioridazine hydrochloride, thiothixene hydrochloride, trimethadione, 
vancomycin hydrochloride and any of their combinations B- for oral 
suspensions--acetopminophen, alumina, magnesia, simethicone, amoxicillin, 
amphotericin B, ampicillin, bacampicillinhydrochloride, bephenium 
hydroxynaphthoate, cefaclor, cefadroxil, cephalexin, cephradine, 
chloramphenicol palmitate, chlorothiazide, chlorprothixene, chlestyramine, 
clavulanate potassium, colestipol hydrochloride, colistin sulfate, 
cyclacillin, demeclocycline, diazoxide, dicloxacillin sodium, doxycycline, 
doxycycline calcium, erythromycin estolate, erythromycin ethylsuccinate, 
erythromycin stearate, erythromycin ethylsuccinate, furazolidone, 
griseofulvin, hetacillin, hydrocortisone cypionate, hydroxyzine pamoate, 
ipodate calcium, levopropoxyphene napsylate, mgaldrate, magnesium 
carbonate, magnesium trisilicate, meprobamtate, methacycline 
hydrochloride, methamine mandelate, methyldopa, minocycline hydrochloride, 
nalidixic acid, nitrofurantoin, novobiocin calcium, nystatin, 
oxytetracycline calcium, penicillin G benzathine, penicillin V, penicillin 
V benzathine, phenytoin, primidone, probenecid, propoxyphene napsylate, 
psyllium hydrophilic mucilloid, pyrantel pamoate, pyrvinium pamoate, 
sulfamethizole, sulfamethoxazole, sulfisoxazole acetyl, tetracycline, 
thiabendazole, thioridazine, triflupromazine, trimethoprim, 
trisulfapyrimidines, troleandomycin and any of their combinations. 
Nanoparticles 
The present invention also has utility to administer and stablize 
nanoparticles wherein the copolymer is absorbed on the surface of the 
nanoparticles. 
Nanoparticles, described in U.S. Pat. No. 5,145,684, are particles 
consisting of a poorly soluble therapeutic or diagnostic agent onto which 
are adsorbed a non-crosslinked surface modifier, and which have an average 
particle size of less than about 400 nanometers (nm). These nanoparticles 
provide for increased bioavailability and for improved diagnostic 
characteristics compared to other materials having larger sizes. 
The nanoparticles can comprise a wide variety of therapeutic or diagnostic 
agents. (Therapeutic agents are sometimes referred to as drugs or 
pharmaceuticals. The diagnostic agent referred to is typically a contrast 
agent such as an x-ray contrast agent but can also be other diagnostic 
materials.) The therapeutic or diagnostic agent exists as a discrete, 
crystalline phase. The crystalline phase differs from a non-crystalline or 
amorphous phase which results from precipitation techniques, such as 
described in EPO 275,796. 
The therapeutic or diagnostic agent preferably is present in an essentially 
pure form. The therapeutic or diagnostic agent must be poorly soluble and 
dispersible in at least one liquid medium. By "poorly soluble" it is meant 
that the therapeutic or diagnostic agent has a solubility in the liquid 
dispersion medium of less than about 10 mg/ml, and preferably of less than 
about 1 mg/ml. A preferred liquid dispersion medium is water. However, the 
invention can be practiced with other liquid media in which a therapeutic 
or diagnostic agent is poorly soluble and dispersible including, for 
example, aqueous salt solutions, safflower oil and solvents such as 
ethanol, t-butanol, hexane and glycol. The pH of the aqueous dispersion 
media can be adjusted by techniques known in the art. 
The described block copolymers can be used with NSAIDS. Surface modified 
nanoparticles comprising an NSAID, e.g., naproxen, demonstrate reduced 
gastric irritation and/or a more rapid onset of action following oral 
administration. 
Useful NSAIDs can be selected from suitable acidic and nonacidic compounds. 
Suitable acidic compounds include carboxylic acids and enolic acids. 
Suitable nonacidic compounds include, for example, nabumetone, tiaramide, 
proquazone, bufexamac, flumizole, epirazole, tinoridine, timegadine and 
dapsone. 
Suitable carboxylic acid NSAIDs include, for example, salicylic acids and 
esters thereof, such as aspirin, diflunisal, benorylate and fosfosal; 
acetic acids, including phenylacetic acids such as diclofenac, alclofenac 
and fenclofenac, and carbo- and heterocyclic acetic acids such as 
etodolac, indomethacin, sulindac, rolmerin, fentiazac and tilomisole; 
propionic acids, such as carprofen, fenbufen, flurbiprofen, ketoprofen, 
oxaprozin, suprofen, tiaprofenic acid, ibuprofen, naproxen, fenoprofen, 
indoprofen, pirprofen; and fenamic acids, such as flufenamic, mefenamic, 
meclofenamic and niflumic. 
Suitable enolic acid NSAIDs include, for example, pyrazolones such as 
oxyphenbutazone, phenylbutazone, apazone and feprazone, and oxicams such 
as piroxicam, sudoxicam, isoxicam and tenoxicam. 
The described nanoparticles can be prepared in accordance with methods 
disclosed in the prior including U.S. Pat. No. 5,145,684 which is 
incorporated by reference herein in. The method of the reference comprises 
the steps of dispersing a therapeutic or diagnostic agent in a liquid 
dispersion medium and applying mechanical means in the presence of 
grinding media to reduce the particle size of the therapeutic or 
diagnostic agent to an effective average particle size of less than about 
400 nm. The particles can be reduced in size in the presence of the 
copolymer. Alternatively, the particles can be contacted with the 
copolymer surface modifier after attrition. 
The therapeutic or diagnostic agent selected is obtained commercially 
and/or prepared by techniques known in the art in a conventional coarse 
form. It is preferred, but not essential, that the particle size of the 
coarse therapeutic or diagnostic agent selected be less than about 100 
.mu.m as determined by sieve analysis. If the coarse particle size of the 
therapeutic or diagnostic agent is greater than about 100 .mu.m, then it 
is preferred that the particles of the therapeutic or diagnostic agent be 
reduced in size to less than 100 .mu.m using a conventional milling method 
such as airjet or fragmentation milling. 
The coarse therapeutic or diagnostic agent selected can then be added to a 
liquid medium in which it is essentially insoluble to form a premix. The 
concentration of the therapeutic or diagnostic agent in the liquid medium 
can vary from about 0.1-60%, and preferably is from 5-30% (w/w). It is 
preferred, but not essential, that the block copolymer be present in the 
premix. The concentration of the block copolymer can vary from about 0.1 
to about 90%, and preferably is 1-75%, more preferably 20-60%, by weight 
based on the total combined weight of the therapeutic or diagnostic agent 
and surface modifier. The apparent viscosity of the premix suspension is 
preferably less than about 1000 centipoise. 
The premix can be used directly by subjecting it to mechanical means to 
reduce the average particle size in the dispersion to less than 400 nm. It 
is preferred that the premix be used directly when a ball mill is used for 
attrition. Alternatively, the therapeutic or diagnostic agent and, 
optionally, the surface modifier, can be dispersed in the liquid medium 
using suitable agitation, e.g., a roller mill or a Cowles type mixer, 
until a homogeneous dispersion is observed in which there are no large 
agglomerates visible to the naked eye. It is preferred that the premix be 
subjected to such a premilling dispersion step when a recirculating media 
mill is used for attrition. 
The mechanical means applied to reduce the particle size of the therapeutic 
or diagnostic agent conveniently can take the form of a dispersion mill. 
Suitable dispersion mills include a ball mill, an attritor mill, a 
vibratory mill, and media mills such as a sand mill and a bead mill. A 
media mill is preferred due to the relatively shorter milling time 
required to provide the intended result, i.e., the desired reduction in 
particle size. For media milling, the apparent viscosity of the premix 
preferably is from about 100 to about 1000 centipoise. For ball milling, 
the apparent viscosity of the premix preferably is from about 1 up to 
about 100 centipoise. Such ranges tend to afford an optimal balance 
between efficient particle fragmentation and media erosion. 
Preparation Conditions for Nanoparticles 
The attrition time can vary widely and depends primarily upon the 
particular mechanical means and processing conditions selected. For ball 
mills, processing times of up to five days or longer may be required. On 
the other hand, processing times of less than 1 day (residence times of 
one minute up to several hours) have provided the desired results using a 
high shear media mill. 
The particles must be reduced in size at a temperature which does not 
significantly degrade the therapeutic or diagnostic agent. Processing 
temperatures of less than about 25.degree.-40.degree. C. are ordinarily 
preferred. If desired, the processing equipment can be cooled with 
conventional cooling equipment. The method is conveniently carried out 
under conditions of ambient temperature and at processing pressures which 
are safe and effective for the milling process. For example, ambient 
processing pressures are typical of ball mills, attritor mills and 
vibratory mills. Control of the temperature, e.g., by jacketing or 
immersion of the milling chamber in ice water are contemplated. Processing 
pressures from about 1 psi (0.07 kg/cm.sup.2) up to about 50 psi (3.5 
kg/cm.sup.2) are contemplated. Processing pressures from about 10 psi (0.7 
kg/cm.sup.2) to about 20 psi (1.4 kg/cm.sup.2) are typical. 
The block copolymer, if it was not present in the premix, must be added to 
the dispersion after attrition in an amount as described for the premix 
above. Thereafter, the dispersion can be mixed, e.g., by shaking 
vigorously. Optionally, the dispersion can be subjected to a sonication 
step, e.g., using an ultrasonic power supply. For example, the dispersion 
can be subjected to ultrasonic energy having a frequency of 20-80 kHz for 
a time of about 1 to 120 seconds. 
After attrition is completed, the grinding media is separated from the 
milled particulate product (in either a dry or liquid dispersion form) 
using conventional separation techniques, such as by filtration, sieving 
through a mesh screen, and the like. 
Particle Size 
As used herein, particle size refers to a number average particle size as 
measured by conventional particle size measuring techniques well known to 
those skilled in the art, such as sedimentation field flow fractionation, 
photon correlation spectroscopy, or disk centrifugation. When photon 
correlation spectroscopy (PCS) is used as the method of particle sizing 
the average particle diameter is the Z-average particle diameter known to 
those skilled in the art. By "an effective average particle size of less 
than about 400 nm" it is meant that at least 90% of the particles have a 
weight average particle size of less than about 400 nm when measured by 
the above-noted techniques. In preferred embodiments, the effective 
average particle size is less than about 300 nm and more preferably less 
than about 250 nm. In some embodiments, an effective average particle size 
of less than about 100 nm has been achieved. With reference to the 
effective average particle size, it is preferred that at least 95% and, 
more preferably, at least 99% of the particles have a particle size less 
than the effective average, e.g., 400 nm. In particularly preferred 
embodiments, essentially all of the particles have a size less than 400 
nm. In some embodiments, essentially all of the particles have a size less 
than 250 nm. 
Liquid Forms 
Liquid dosage forms for administration of the present invention include 
pharmaceutically acceptable emulsions, solutions, suspensions, syrups and 
elixirs. In addition to the active compounds, the liquid dosage forms may 
contain inert diluents commonly used in the art, such as water or other 
solvents, solubilizing agents and emulsifiers, as for example, ethyl 
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl 
alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, 
dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, 
corn germ oil, olive oil, castor oil and sesame oil, glycerol, 
tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of 
sorbitan or mixtures of these substances, and the like. 
Topical Forms 
Dosage forms for topical administration, including opthalmic, of the 
present invention include solutions, sprays and inhalants. The active 
component is admixed under sterile conditions with a physiologically 
acceptable carrier and any preservatives, buffers or propellants as may be 
required. 
Dosage Levels 
Actual dosage levels of active ingredients in the compositions may be 
varied so as to obtain an amount of active ingredient that is effective to 
obtain a desired therapeutic or diagnostic response for a particular 
composition and method of administration. The selected dosage level 
therefore depends upon the desired therapeutic or diagnostic effect, on 
the route of administration, on the desired duration of treatment and 
other factors. 
The total daily dose administered to a host in single or divided dose may 
be in amounts, for example, of from about 1 nanomol to about 5 micromoles 
per kilogram of body weight. Dosage unit compositions may contain such 
amounts of such submultiples thereof as may be used to make up the daily 
dose. It will be understood, however, that the specific dose level for any 
particular patient will depend upon a variety of factors including the 
body weight, general health, sex, diet, time and route of administration, 
rates of absorption and excretion, combination with other therapeutic 
agents and the severity of the particular disease being treated. 
Additives 
Besides such inert diluents, the composition can also include buffers, 
adjuvants, such as wetting agents, emulsifying and suspending agents, 
sweetening, flavoring and perfuming agents. 
Suspensions, in addition to the active compounds, may contain suspending 
agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene 
sorbitol and sorbitan esters, microcrystalline cellulose, aluminum 
metahydroxide, bentonire, agar-agar and tragacanth, or mixtures of these 
substances, and the like. 
These compositions may also contain adjuvants such as preserving, wetting, 
emulsifying, and dispensing agents. Prevention of the action of 
microorganisms can be measured by various antibacterial and antifungal 
agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the 
like. It may also be desirable to include isotonic agents, for example 
sugars, sodium chloride and the like. Prolonged absorption of the 
pharmaceutical form can be brought about by the use of agents delaying 
absorption, for example, aluminum monostearate and gelatin. 
Method of Treating 
A method of treating or diagnosing a mammal comprises the step of 
administering to the mammal in need of treatment an effective amount of 
the above-described therapeutic or diagnostic agent composition. The 
selected dosage level of the therapeutic or diagnostic agent for treatment 
is effective to obtain a desired therapeutic or diagnostic response for a 
particular composition and method of administration. The selected dosage 
level therefore, depends upon the particular therapeutic or diagnostic 
agent, the desired therapeutic or diagnostic effect, on the route of 
administration, on the desired duration of treatment and other factors. 
It is contemplated that the therapeutic or diagnostic compositions will be 
particularly useful in oral, subcutaneous, topical, ophthalmic and nasal 
administration applications. It is expected that even poorly water soluble 
therapeutic or diagnostic agents may be administered safely. Additionally, 
therapeutic or diagnostic agents which could not have been administered 
orally due to poor bioavailability may now be effectively administered. 
The following Preparation illustrates the preparation of a block polymer 
that is useful in the present invention. 
Preparation of the Preferred Copolymer 
First Preparation 
An oxymethylene linked, multiblock copolymer was prepared by the reaction 
of an E.sub.141 P.sub.44 E.sub.141 triblock copolymer of poly(oxyethylene) 
(E.sub.141) and poly(oxypropylene) (P.sub.44), having an average molecular 
weight of 14,500, (Pluronic.TM. 108) with dichloromethane in the presence 
of potassium hydroxide. 
Finely ground potassium hydroxide (66 g) was mixed with dichloromethane 
(300 mL) under a nitrogen atmosphere at room temperature in a one liter 
resin kettle equipped with a condenser and a mechanical stirrer. To this 
was added the triblock copolymer (100 g) dispersed in dichloromethane (700 
mL). 
The whole was stirred for approximately two hours, then additional 
dichloromethane (500 mL) was added to reduce the viscosity of the polymer 
solution. The solution was filtered through a pad of Celite.TM. 
(Kieselguhr) and then rotary evaporated under vacuum to give a polymer. 
The polymer was characterised by gel permeation chromatography (GPC). 
Dimethyl formamide (DMF) eluant and styragel columns were employed, 
calibrated with poly(oxyethylene) standards. Molecular weights and 
molecular weight distributions were obtained from the GPC curve by 
reference to this calibration. The preparation was repeated three times 
with average molecular weights ranging 50,824 to 68,092. The gel point at 
4% concentration ranged from 33.degree. to 36.degree. C. 
Second Preparation 
A block polymer having the structure as follows was prepared. 
EQU --(E.sub.141 P.sub.44 E.sub.141)CH.sub.2 O!.sub.4 to 8 
--(E.sub.1)CH.sub.2 O!.sub.4-8 
wherein 
P is oxypropylene; and 
E is oxyethylene. 
Pluronic.TM. F108, as used in the first preparation, and polyethylene 
glycol (PEG6000- 50 g) were dissolved in dichloromethane and added rapidly 
to a stirred suspension of powdered sodium hydroxide (100 g) in 
dichloromethane (275 mL) and stirred under nitrogen for 15-18 hours. The 
mixture was diluted with dichloromethane (1200 mL), allowed to settle and 
filtered through a Celite pad to remove inorganics. The solvent is then 
evaporated. 
The product polymer has an average molecular weight of about 143,000, based 
on the average of three preparation batches, and a gel point of 37.degree. 
C. (4% concentration in deionized water. 
Example 1: Solution for Ophthalmic, Nasal and Oral Application: 
3% w/w (however, 1% to 6% may be used, and preferable 2% to 3%) of the most 
preferred copolymer of the above Second Preparation, is added to 
commercial products of cromolyn sodium for nasal application, 
acetylcholine chloride for ophthalmic application and vanomycin for oral 
application. 
The mixtures are allowed to stirred at room temperature overnight in a 
sanitized area followed by filtration through a 0.2 micron filter. 
When the solutions are administered to the eye, to the nose or orally, they 
form a gel. 
Example 2: Suspension for Ophthalmic Application: 
A suspension of chloramphenicol is subjected to centrifugation at 15,000g 
in a close sterile centrifugation container. The supernatant and the drug 
pellet are collected aseptically in a laminar flow hood. To the 
supernatant, 4% of the preferred copolymer of the above Second 
Preparation, is added (however, 1% to 6%, preferably 3% to 5% w/w may be 
used). The mixture is stirred overnight at room temperature for 
dissolution. Operating inside a laminar flow hood, the dissolved thermal 
gel solution was filtered through a 0.2 micron filter into the drug pellet 
to provide the ophthalmic suspension. 
Upon ophthalmic application, the suspension gels; thereby keeping the drug 
substance in contact with the eye. 
Example 3: Suspension for Oral Application: 
4% w/w (1% to 6%, preferably, 3% to 5% may be used) of the preferred 
copolymer of the above Second Preparation, is added to a suspension of 
acetaminophen. The mixture is stirred overnight at room temperature in a 
sanitized area to provide the suspension for oral application. 
Upon oral administration the suspension gels. 
Example 4: Solution Preparation from Drug Substances for Ophthalmic 
Application: 
Timolol maleate is used as a model compound. 
5% w/v (1% to 6%, preferably 3% to 5% may be used) of the preferred 
copolymer of the above Second Preparation, and 0.1% w/v benzalkonium 
chloride is allowed to dissolved in phosphate balance buffer by stirring 
overnight at room temperature. Timolol maleate at a concentration of 6.8 
mg/ml is dissolved into the preferred copolymer/benzalkonium chloride. The 
solution is then sterile filtered through a 0.2 micron filter aseptically 
before use. 
Upon ophthalmic administration the solution gels. 
Example 5: Solution Preparation from Drug Substance for Nasal Application: 
Phenylephrine hydrochloride is used as a model compound. 
3% w/v (however, 1% to 6%, preferably 2% to 4% may be used) of the 
preferred copolymer of the above Second Preparation, phenylephrine 
hydrochloride at 0.5% and pheniramine maleate at 0.2% were dissolved in 
PBS containing 0.4% alcohol and 0.02% benzalkonium chloride. 
Upon nasal administration the solution gels. 
The invention has been described with particular reference to preferred 
embodiments thereof, but it will be understood that variations and 
modifications can be effected within the spirit and scope of the 
invention.