Note: Descriptions are shown in the official language in which they were submitted.
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ELECTROSPUN PHARMACEUTICAL COMPOSITIONS
FIELD OF THE INVENTION
This invention relates to nanofibers of drug particles, method of preparation
thereof
and pharmaceutical compositions containing these nanofibers. This invention
further relates to the use of such nanofibers in designing various dosage
forms to .
achieve maximum bioavailability of a drug moiety.
BACKGROITND OF THE INVENTION
It is known that the rate of dissolution of a particulate drug can increase
with
increasing surface area, i.e., decreasing particle size. Consequently, methods
of
making finely divided drugs have been studied and efforts have been made to
control
the size and size range of drug particles in pharmaceutical compositions. For
example, dry milling techniques have been used to reduce particle size and
hence
influence drug absorption. However, in conventional dry milling, as discussed
by
Lachman, et al., The Theory and Practice of Industrial Pharmacy, Chapter 2,
"Milling", p. 45, (1986), the limit of fineness is reached in the region of
100 microns
( 100,000 nm) when material cakes on the milling chamber. Lachman, et al. note
that
wet grinding is beneficial in further reducing particle size, but that
flocculation
restricts the lower particle size limit to approximately 10 microns (10,000
nm).
However, there tends to be a bias in the pharmaceutical art against wet
milling due
to concerns associated with contamination. Commercial airjet milling
techniques
have provided particles ranging in average particle size from as low as about
1 to 50
micrometers (1,000-50,000 nm).
Other techniques for preparing pharmaceutical compositions include loading
drugs
into liposomes or polymers, e.g., during emulsion polymerization. However,
such
techniques have problems and limitations. For example, a lipid soluble drug is
often
required in preparing suitable liposomes. Further, unacceptably large amounts
of the
liposome or polymer are often required to prepare unit drug doses. Further
still,
techniques for preparing such pharmaceutical compositions tend to be complex.
A
principal technical difficulty encountered with emulsion polymerization is the
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removal of contaminants, such as unreacted monomer or initiator, which can be
toxic, at the end of the manufacturing process.
U.S. Pat. No. 4,540,602 (Motoyama et al.) discloses a solid drug pulverized in
an
aqueous solution of a water-soluble high molecular substance using a wet
grinding
machine. However, Motoyama et al. teach that as a result of such wet grinding,
the
drug is formed into finely divided particles ranging from 0.5 µm (500 nm)
or less
to 5 µm (5,000 nm) in diameter.
US Patent No. 5,145,684 (Liversidge et al) discloses dispersible crystalline
drug
substances having particle sizes lower than 400nm, for increased
bioavailability,
produced by wet milling.
EPO 275,796 describes the production of colloidal dispersible systems
comprising a
substance in the form of spherical particles smaller than 500 nm. However, the
method involves a precipitation effected by mixing a solution of the substance
and a
miscible non-solvent for the substance and results in the formation of non-
crystalline
nanoparticle. Furthermore, precipitation techniques for preparing particles
tend to
provide particles contaminated with solvents. Such solvents are often toxic
and can
be very difficult, if not impossible, to adequately remove to pharmaceutically
acceptable levels to be practical.
U.S. Pat. No. 4,107,288 describes particles in the size range from 10 to 1,000
nm
containing a biologically or pharmacodynamically active material. However, the
particles comprise a crosslinked matrix of macromolecules having the active
material supported on or incorporated into the matrix.
Solid dispersions of drugs in polymers are being investigated to address the
diminished bioavailability of poorly water soluble drugs. For a recent review
see
Serajuddin, Journal of Pharmaceutical sciences, 1999, 88(10), 1058.
An area of great interest is the rapid dissolve dosage forms, which is
targeted
towards the specific needs of pediatric, geriatrics and patients with
dysphagia.
U.S. Pat. No. 4,855,326 describes a melt spinnable carrier agent such as sugar
is
combined with a medicament then converted into fiber form by melt spinning
with
"cotton candy" fabricating equipment. The as-spun product is converted to
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compacted individual dosage units. For certain medicaments a binding agent is
added to the carrier agent. Examples are presented for oral administration,
topical
application, systemic and non-systemic, intravenous and infra-muscular
infusion via
multicameral containers. All applications utilize the extraordinarily rapid
entry into
solution upon contact with a solvent.
U.S. Pat. Nos. 4,946,684; 5,298,261; 5,466,464; 5,501,861; 5,762,961;
5,866,163
disclose taste masked rapidly dissolving dosage forms having organoleptically
acceptable properties disintegrate rapidly in patients mouth without chewing
or with
minimum amount of water.
U.S. Pat. No. 5,948,430 discloses a polymeric film composition providing
instant
wetability followed by rapid dissolution/disintegration upon administration in
the
oral cavity. This may be applicable only to soluble drugs.
Pulmonary delivery, both as immediate and modified release, dosage forms are
being
actively investigated.
U.S. Pat. No. 5,747,001 discloses the advantages of aerosolized nanoparticles
in
pulmonary delivery.
WO 99/48476 describes the use of drug/carrier particles having elongation
ratio
greater than 1.6 for improved delivery by inhalation. Such particles are
either
produced by SCF technique or by a complex precipitation process.
Electrospinning
provides a direct, scalable process for the production of nanoparticles having
greater
elongation ratios.
US 5, 985,309 discloses large porous biodegradable microspheres containing
proteins and peptides for pulmonary delivery.
It would be desirable to design a simple pharmaceutical composition which
provides
for all the positive attributes of the above dosage forms by combining the
enhanced
bioavailability of nanoparticles and physico-chemical characteristics of a
nanofiber
in a polymeric carrier matrix, in which the drug nanoparticles are
homogeneously
embedded, such that a convenient dosage form such as a rapid dissolve,
immediate,
delayed, modified release could be produced by simply selecting the
appropriate
polymer, without having to change the process.
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SUMMARY OF THE INVENTION
One object of the present invention is a process for electrospinning a
pharmaceutically acceptable active agent, or agents, in the presence of a high
molecular weight polymeric carrier that acts as viscosity enhancer and fiber
forming
agent. The process of making the electrospun pharmaceutical composition may be
from a solution or a melt.
The present invention is also directed to a pharmaceutical composition
comprising
an electrospun fiber of a pharmaceutically acceptable polymeric carrier
integrated
with a pharmaceutically acceptable active agent.
The present invention is also directed to use of an electrospun pharmaceutical
composition comprising a pharmaceutically acceptable active agent, and a
pharmaceutically acceptable polymeric carrier directly for oral
administration,
pulmonary administration, or for dissolution into a liquid media for
administration,
such as a suspension or solution or by parenteral/intramuscular or
intracavernosum
injection.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 demonstrates electrospinning of viscous drug/polymer compositions
either
in solution or in melt form to produce nanofibers.
Figure 2 shows the dissolution rate of nanofibers containing nabumetone
normalized
with respect to nanoparticles of nabumetone.
Figure 3 shows a scanning electron microscope (SEM) of 60% w/w nabumetone
spun with POLYOX~ fibers.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a novel composition of an electrospun
fiber
which fiber is the result of a high molecular weight polymeric carrier that
acts as
viscosity enhancer and fiber forming agent, and which carrier is spun with a
pharmaceutically acceptable agent or drug.
As used herein the term "integrated" means that the drug is integrated with,
admixed
with, comingled with, or intermixed with the carrier. It is not coated on the
surface
of an electrospun fiber (woven or non-woven). Specifically the fiber contains
both
the agent and the carrier together, preferably in a homogeneous manner. While
it is
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recognized that incomplete stirring of the solutions or the neat/melted
compositions
may result in some heterogenicity of the resultant fiber, the premise is that
the drug
and the carrier are spun together, rather than being applied in a later step
to a fiber.
The electrospun fibers of the present invention are expected to have diameters
in the
nanometer range, and hence provide a very large surface area. The process
generates
fibers where a high surface to volume ratio is important. This extremely high
surface area has profound influence on the bioavailability of a poorly water
soluble
drug, since it is known that increased surface can lead to increased
dissolution rate.
A suitable dosage form, such as oral or parenteral form, including pulmonary
administration, may be designed by judicious consideration of polymeric
carriers, in
terms of their physico-chemical properties as well as their regulatory status.
Other
pharmaceutically acceptable excipients may be included to ameliorate the
stabilization or de-agglomeration of the drug nanoparticles. The
pharmaceutical
excipients might also have other attributes, such as absorption enhancers.
Electrospun pharmaceutical dosage form may be designed to provide rapid
dissolution, immediate, delayed, or modified dissolution, such as sustained
and /or
pulsatile release characteristics.
Taste masking of the active agent can also be achieved by using polymers
having
functional groups capable of promoting specific interactions with the drug
moiety.
The electrospun dosage forms may be presented as compressed tablets, sachets
or
films. Conventional dosage forms such as immediate, delayed and modified
release
systems can be designed by appropriate choice of the polymeric carrier, drug
combination, as described in the art.
It is one object of the present invention to provide pharmaceutically
acceptable drug
nanoparticles embedded homogeneously in polymeric nanofibers, such that the
drug
readily bioavailable independent of the route of administration.
Electrospinning, commonly referred to as electrostatic spinning, is a process
of
producing fibers, with diameters in the range of 100nm. The process consists
of
applying a high voltage to a polymer solution or melt to produce a polymer
jet. As
the jet travels in air, the jet is elongated under repulsive electrostatic
force to produce
nanofibers. The process has been described in the literature since the 1930. A
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variety of polymers both natural and synthetic having optimal characteristics
have
been elctrospun under appropriate conditions to produce nanofibers, (see
Reneker et
al., Nanotechnology, 1996, 7, 216). Different applications have been suggested
for
these electrospun nanofibers, such as air filters, molecular composites,
vascular
grafts, and wound dressings.
U.S. Patent No. 4,043,331, is intended for use as a wound dressing whereas
U.S.
Patent No. 4,044,404, and US Patent No. 4,878,908 are tailored towards
creating a
blood compatible lining for a prosthetic device. All of the disclosed water
insoluble
polymers are not pharmaceutically acceptable for use herein, however the water
soluble polymers disclosed are believed to be pharmaceutically acceptable.
None of
the preparations in these patents disclose a working example of an electrospun
fiber
with an active agent. The patents claim the use of enzymes, drugs and/or
active
carbon on the surface of the nanofibers, prepared by immobilizing the active
moieties so that they act at the site of application and "do not percolate
throughout
the body".
EP 542514, US 5,311,884 and US 5,522,879 pertain to use of spun fibers for a
piezoelectric biomedical device. The piezoelectric properties of fluorinated
polymers, such as those derived from a copolymer of vinylidene fluoride and
tetrafluoroethylene are not considered pharmaceutically acceptable polymers
for use
herein.
US Patent 5,024,671 uses the electrospun porous fibers as a vascular graft
material
which is filled with a drug in order to achieve a direct delivery of the drug
to the
suture site. The porous graft material is impregnated (not electrospun) with
the drug
and a biodegradable polymer is added to modulate the drug release. The
vascular
grafts are also made from non-pharmaceutically acceptable polymers, such as
the
polytetrafluorethylene or blends thereof.
US Patent No. 5,376,116, US Patent No. 5,575,818, US Patent No. 5,632,772, US
Patent No. 5,639,278 and US Patent No. 5,724,004 describe one form or another
of a
prosthetic device having a coating or lining of an electrospun non-
pharmaceutically
acceptable polymer. The electrospun outer layer is post-treated with a drug
such as
disclosed in the '116 patent (for breast prosthesis). The other patents
describe the
same technology and polymers but apply the technique to other applications,
such as
endoluminal grafts or endovascular stems.
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Consequently, the present invention is the first to produce a pharmaceutical
composition of an active agents) and a pharmaceutically acceptable polymer as
an
electrospun fiber. The homogenous nature of this process produces a quantity
of
fibers which allow for nanoparticles of drugs to be dispersed throughout. The
size of
particle, and quality of dispersion provide for a high surface area of drug.
One use
of the increased surface area of drug is improved bioavailability in the case
of a
poorly water soluble drug. Other uses would be for decreased drug-drug or
enzymatic interactions.
The present invention is therefore directed to use in any form of a
nanofibrous drug
either alone, or in combination with a pharmaceutically acceptable polymer (or
combination thereof) for enhancing the bioavailability of a drug, preferably a
poorly
water soluble drug.
The present invention is also directed to a rapidly dissolving dosage form
comprising
an electrospun water soluble polymer in combination with an active agent, such
that
the rapid dissolving dosage form disintegrates in a rapid manner, over a short
time
period, in the mouth or other suitable body cavity. In the oral context this
would
produce small particulate matter, which could be ingested without needing
water.
A rapid dissolve dosage form may include a drug which is either water soluble
or
water insoluble. A rapid onset of action is a not prerequisite for a rapid
dissolve
dosage form. For a bitter tasting drug it may be advantageous to have it in an
insoluble form, either by its own solubility characteristics or by polymer
coating.
Therefore, the main attribute of a rapid dissolve dosage form is that the
excipients
rapidly disintegrate in the mouth, exposing the drug particles to be easily
swallowed.
This being the case, electrospun polymer (water-soluble) nanofibers may
suitably be
premixed with drug during spinning or post mixed during fabrication of the
rapid
dissolve dosage form.
While the application of this process may be of use for incorporation of a
pharmaceutically acceptable drug for topical delivery, it is primarily
oriented
towards oral, intravenous, intramuscular, or inhalation usage.
Pharmaceutically acceptable agents, actives or drugs as used herein, is meant
to
include active agents having a pharmacological activity for use in a mammal,
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preferably a human. The pharmacological activity may be prophylactic or for
treatment of a disease state. The usage is not meant to include agricultural
or
insecticide usage for application to plants or soil. Use of the electrospun
fiber as a
woven or non-woven fabric for direct application as a topical treatment in
wound
dressing or in clothing is also not an aspect of the present invention.
However, use
of the fibers in a pharmaceutical formulation for topical administration are
considered within the scope of the present invention.
As used herein the term's "active agent'°, "drug moiety" or "drug"
are used
interchangeably.
Water solubility of the active agent is defined by the United States
Pharmacoepia.
Therefore, active agents which meet the criteria of very soluble, freely
soluble,
soluble and sparingly soluble as defined therein are encompassed this
invention. It is
believed that the electrospun polymeric composition which most benefit those
drugs
which are insoluble or sparingly soluble.
Suitable drug substances can be selected from a variety of known classes of
drugs
including, for example, analgesics, anti-inflammatory agents, anthelmintics,
anti-
arrhythmic agents, antibiotics (including penicillin's), anticoagulants,
antidepressants, antidiabetic agents, antiepileptics, antihistamines,
antihypertensive
agents, antimuscarinic agents, antimycobactefial 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, corticosteroids, cough
suppressants (expectorants and mucolytics), diagnostic agents, diuretics,
dopaminergics (antiparkinsonian agents), haemostatics, immunological agents,
lipid
regulating agents, muscle relaxants, parasympathomimetics, parathyroid
calcitonin
and biphosphonates, prostaglandins, radiopharmaceuticals, sex hormones
(including
steroids), anti-allergic agents, stimulants and anorexics, sympathomimetics,
thyroid
agents, PDE IV inhibitors, NK3 inhibitors, CSBP/RK/p3g inhibitors,
antipsychotics,
vasodilators and xanthines.
Preferred drug substances include those intended for oral administration and
intravenous administration. A description of these classes of drugs 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 disclosure
of
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which is hereby incorporated herein by reference in its entirety. The drug
substances
are commercially available and/or can be prepared by techniques known in the
art.
As noted, the electrospun composition may also be able to taste mask the many
bitter
or unpleasant tasting drugs, regardless of their solubility. Suitable active
ingredients
for incorporation into fibers of the present invention include the many bitter
or
unpleasant tasting drugs including but not limited to the histamine H~-
antagonists,
such as, cimetidine, ranitidine, famotidine, nizatidine, etinidine;
lupitidine,
nifenidine, niperotidine, roxatidine, sulfotidine, tuvatidine and zaltidine;
antibiotics,
such as penicillin, ampicillin, amoxycillin, and erythromycin; acetaminophen;
aspirin; caffeine, dextromethorphan, diphenhydramine, bromopheniramine,
chloropheniramine, theophylline, spironolactone, NSAmS's such as ibuprofen,
ketoprofen, naprosyn, and nabumetone; 5HT3 inhibitors, such as granisetron
(Kytril~), or ondansetron (Zofran~); seratonin re-uptake inhibitors, such as
paroxetine, fluoxetine, fluvoxamine, and sertraline; vitamins such as ascorbic
acid,
vitamin A, and vitamin D; dietary minerals and nutrients, such as calcium
carbonate,
calcium lactate, etc., or combinations thereof.
Suitably, the above noted active agents, in particular the anti-inflammatory
agents,
may also be combined with other active therapeutic agents, such as various
steroids,
decongestants, antihistamines, etc., as may be appropriate.
Preferably, the active agent is nabumetone, cis-4-Cyano-4-[3-cyclopentyloxyl)-
4
methoxyphenyl]cyclohexanecarboxylic acid, ASA, paroxetine (Seroxat~), Ariflo,
ropirinole (Requip~), rosiglitazone (Avandia~), or hydrochlorothyazie and
traimeterene (Dyazide~).
Other suitable active agents are amprenavir (Agenerase~), lamivudine (Epivir
~),
epoprostenol (Flolan~), zanamivir (Relenza~), alosetron (Lotronex~),
alclometasone (Aclovate~), beclomethasone (Beclovent~ and Beconase~),
malphalan (Aleran~), naratriptan (Amerge ~), succinylcholine, cefuroxiime
(Ceftin~), ceftazidime (Ceptaz~), cefuroxime (Zinacef~), zidovudine
(Retrovir~),
fluticasone (Flonase~ or Cutivate~), pyrimethamine (Daraprim~), colfosceril,
sumatriptan (Imitrex~), lamotrigine (Lamictal~), chlorambucil (Leukeran~),
atovaquone (Malaron~ or Mepron ~), mivacurium (Mivacron~), busulfan
(Myleran~), vinorelbine (Navelbine~), cisatracurium (Nimbex~), doxacurium
(Nuromax~), atacurium (Tracrium~), oxiconazole (Oxistat~), mercaptopurine
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(Purinethol~) and thioguanine (Tabloid~), grepafloxacin (Raxar~), salmeterol
(Serevent~), clobetasol (Temovate~), ranitidine, famotidine, omeprazole (R and
S
isomers), remifentanil (Ultiva~), valacyclovir (Valtrex~), acyclovir
(Zovirax~),
famciclovir (Famvir~), penciclovir (Denavir~), albuterol (Ventolin~),
bupropion
(Wellbutrin~ or Zyban~), or abacavir (Ziagen~), 4-(3,4-dihydro-1-methyl-2(1H)-
isoquinolinyl)-N-(4-fluorophenyl)-5,6-dimethyl-2-pyrimidinamine, (N-(2,6-
dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine) ; telmisartan,
lacidipine, eniluracil, amoxicillin (Amoxcil~), clavulanate, mupirocin,
ticarcillin,
cerivastatin (Baycol~), carvedilol (Coreg~), topotecan (Hycamtin~), Factive~,
Locilex~, Novastan~, Tranilast, Lotrifiban, 8-[(4-Amino-1-methylbutyl)amino]-
2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline succinate, '
1 S,2R,3S)-1-( 1,3-Benzodioxol-5-yl)-2,3-dihydro-3-[2-(2-hydroxyethoxy)-4-
methoxyphenyl]-5-propoxy-1H-indene-2-carboxylic acid, nelarabine, dutasteride,
maribavir , 3-(3-{ 1-[(Isopropyl-phenyl-carbamoyl)-methyl]-2,4-dioxo-5-phenyl-
- '2,3°,4;5=tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}-ureido)-benzoic
acid; 6-amino-
3-(2;3,5-trichlorophenyl)pyrazin-2-ylamine; (2R,3R,4S,5R)-2-[6-Amino--2-(1S-
hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-
tetrahydro-furan-3,4-diol; (6x,11 (3, l6oc,17a)-6,9-difluoro-11-hydroxy-16-
methyl-3-
oxo-17-( { [ ( 3 S )-2-oxotetrahydrofuran-3-yl] thio } carbonyl) andro sta-1,4-
then-17-yl
propionate; (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl]
(isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate; (3R,5R)-3-Butyl-3-
ethyl-7,8-dimethoxy-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine l,l-
dioxide;
( 1 S,3S,4S,8R)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3Ø04°8] decan-
5-ol;
(2S,3S,5R)-2-(3,5-Difluorophenyl)-3,5-dimethyl-2-morpholinol; (S)-2-(2-Benzoyl-
phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic
acid; 3'-[(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}ethyl)amino] [1,1'-
biphenyl]-3-carboxylic acid; (2S)-2-{ [(1Z)-1-methyl-3-oxo-3-phenylprop-1-
enyl]amino }-3-{ 4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl
}propanoic
acid; or combinations and mixtures thereof of all compounds noted herein.
In short, for use herein, a poorly soluble drug should have good solubility in
an
organic solvent, or a poorly soluble drug must be useable in a melt process as
further
described below.
The nanofibers of this invention will contain high molecular weight polymeric
carriers. These polymers, by virtue of their high molecular weight, form
viscous
solutions which can produce nanofibers, when subjected to an electrostatic
potential.
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Suitable polymeric carriers can be preferably selected from known
pharmaceutical
excipients. The physico-chemical characteristics of these polymers dictate the
design of the dosage form, such as rapid dissolve, immediate release, delayed
release, modified release such as sustained release, or controlled release,
pulsatile
release etc.
DNA fibers have been used to form fibers by electrospinning, Fang et al., J.
Macromol. 5ci.-Phys., B36(2), 169-173 (1997). Incorporation of a
pharmaceutically
acceptable active agent, such as a biological agent, a vaccine, or a peptide,
with
DNA, RNA or derivatives thereof as a spun fiber is also within the scope of
this
invention.
The fiber forming characteristics of the polymer are exploited in the
fabric~.tion of
nanofibers. Hence, molecular weight of the polymer is the single most
important
:parameter for choice of polymer. As previously noted, a large number of
polymers
have already been electrospun, such as cellulose acetate, PVA, PEO, PVP,
polyacrylamide, polyurethane, polycarbonate, PTFE, PE, PP, polyacrylate,
I~evlar,
PHB, polyaniline, DNA, poly (phenylene terphthalamide) and silk.
However, for purposes herein additional representative examples of polymers
suitable for pharmaceutical applications, include, but are not limited to,
polyethylene oxide), polyvinyl alcohol, polyvinyl acetate, polyvinyl
pyrrolidone,
hyaluronic acid, alginates, carragenen, cellulose derivatives such as
carboxymethyl
cellulose sodium, methyl cellulose, ethylcellulose, hydroxyethyl cellulose,
hydroxypropylcellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl
cellulose phthalate, cellulose acetate phthalate, noncrystalline cellulose,
starch and
its derivatives such as hydroxyethyl starch, sodium starch glycolate, chitosan
and its
derivatives, albumen, gelatin, collagen, polyacrylates and its derivatives
such as the
Eudragit family of polymers available from Rohm Pharma, poly(alpha-hydroxy
acids) and its copolymers such poly(caprolactone), poly(lactide-co-glycolide),
poly(alpha-aminoacids) and its copolymers, poly(orthoesters),
polyphosphazenes,
poly(phosphoesters), and polyanhydrides, or mixtures thereof.
Most of these pharmaceutically acceptable polymers are described in detail in
the
Handbook of Pharmaceutical excipients, published jointly by the American
Pharmaceutical association and the Pharmaceutical society of Britain.
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Preferably, the polymeric carriers are divided into three categories: (1)water
soluble
polymers useful for rapid dissolve and immediate release of active agents, (2)
water
insoluble polymers useful for controlled release of the active agents; and (3)
pH
sensitive polymers for pulsatile or targeted release of active agents. It is
recognized
that combinations of both carriers may be used herein. It is also recognized
that
several of the polyacrylates are pH dependent for the solubility and may fall
into
both categories.
Water soluble polymers include but are not limited to, polyethylene oxide),
' polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, alginates,
carragenen,
cellulose derivatives such as carboxymethyl cellulose sodium; hydroxyethyl
cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose,
hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, starch
and its
derivatives such as hydroxyethyl starch, sodium starch glycolate, dextrin,
chitosan
and its derivatives, albumen, zero, gelatin, and collagen.
Preferably, a water soluble polymer for use herein is polyethylene oxide, such
as the
brand name POLYOX~. It is recognized that the polymers may be used in varying
molecular weights, with combinations of molecular weights for one polymer
being
used, such as 100K, 200K, 300K, 400K, 900K and 2000K. Sentry POLYOX is a
water soluble resin which is listed in the NF and have approximate molecular
weights from 100K to 900K and 1000K to 7000K. These commercially available
polymers may be used as 1 %, 2% and 5% solutions (depending upon molecular
weight).
NF grades of Sentry POLYOX, a water soluble resin is available with varying
molecular weights as noted above. A table, shown below, provides further
information on the grade vs. approx. molecular weight for use in the examples
herein.
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Viscosity
range at
25 C, cP
NF Grade Approximate5% solution2% solution 1% solution
mol. wei
ht
WSRN-10 100,000 30-50
WSRN-80L 200,000 500
WSRN-80H 200,000 90-105
WSRN-750 300,000 500-1200
WSRN-3000 400,000 1,250-4,500
WSR-20S 600,000 4,500-8,800
WSR-1105 900,000 8,800-17,600
WSRN-12K 1,000,000 400-800
WSRN-60K 2,000,000 ~ 2,000-4,000
WSR-301 4,000,000 1,500-4,500
WSR coagulant5,000,000 4,500-7,500
WSR-303 7,000,000 7,500-
10,000
Additional preferred polymers include povidone, having K values and molecular
weight ranges from
K value Mol. wt.
12 25
15 8000
17 10,000
25 30,000
30 50,000
60 400K
90 1000K
120 3000K
Water insoluble polymers include but are not limited to, polyvinyl acetate,
methyl
cellulose, ethylcellulose, noncrystalline cellulose, polyacrylates and its
derivatives
such as the Eudragit family of polymers available from Rohm Pharma (Germany),
poly(alpha-hydroxy acids) and its copolymers such as poly(-caprolactone),
poly(lactide-co-glycolide), poly(alpha-aminoacids) and its copolymers,
poly(orthoesters), polyphosphazenes, poly(phosphoesters), and polyanhydrides.
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These pharmaceutically acceptable polymers and their derivatives are
commercially
available and/or be prepared by techniques known in the art. By derivatives it
is
meant, polymers of varying molecular weight, modification of functional groups
of
the polymers, or co-polymers of these agents, or mixtures thereof.
Further, two or more polymers can be used in combination to form the fibers as
noted herein. Such combination may enhance fiber formation or achieve a
desired
drug release profile.
The choice of polymers taken with the active agent may provide suitable taste
masking functions for the active agents. For instance; use of an ionic polymer
of
contrasting charge, such as a cationic polymer complexed with an anionic
active
agent, or an anionic polymer complexed with a cationic active agent may
produce
the desired results. Addition of a second taste masking agent; such as a
suitable
cyclodextrin, or its derivatives may also ~be used herein:
The polymeric composition may be electrospun from a solvent base or neat (as a
melt). Solvent choice is preferably based upon the solubility of the active
agent.
Suitably, water is the best solvent for a water soluble active agent, and a
water
soluble polymer like POLYOX. Alternatively, water and a water-miscible organic
solvent may used. However, it is necessary to use an organic solvent to
prepaxe a
homogenous solution of the drug with polymer when the drug is non-water
soluble,
or sparingly soluble.
It is recognized that these polymeric composition which are spun neat may also
contain additional additives such as, plasticizers. The plasticizers are
employed to
assist in the melting characteristics of the composition. Exemplary of
plasticizers
that may be employed in this invention are triethyl citrate, triacetin,
tributyl citrate,
acetyl triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, dibutyl
sebacate, vinyl
pyrrolidone, propylene glycol, glycol tiracetate, polyethylene glycol, or
polyoxyethylene sorbitan monolaurate and combinations or mixtures thereof.
Preferably, the solvent of choice is a GRASS approved organic solvent,
although the
solvent may not necessarily be "pharmaceutically acceptable" one, as the
resulting
amounts may fall below detectable, or set limits for human consumption they
may be
used. It is suggested that ICH guidelines be used for selection. GRASS in an
anacronym for "generally recognized as safe".
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Suitable solvents for use herein include, but are not limited to acetic acid,
acetone,
acetonitrile, methanol, ethanol, propanol, ethyl acetate, propyl acetate,
butyl acetate,
butanol, N,N dimethyl acetamide, N,N dimethyl formamide, 1-methyl-2-
pyrrolidone, dimethyl sulfoxide, diethyl ether, disisopropyl ether,
tetrahydrofuran,
pentane, hexane, 2-methoxyethanol, formamide, formic acid, hexane, heptane,
ethylene glycol, dioxane, 2-ethoxyethanol, trifluoroacetic acid, methyl
isopropyl
ketone, methyl ethyl ketone, dimethoxy propane, methylene chloride etc., or
mixtures thereof.
A preferred solvent is a mixture of water and acetonitrile, or water and
acetone.
The solvent to polymeric composition ratio is. suitable determined by the
desired
viscosity of the resulting formulation.
For electrospinning of a pharmaceutical polymeric composition, key parameters
are
viscosity, surface tension, and electrical conductivity of the
solvent/polymeric
composition. '
By the term "nanoparticulate drug" as used herein, is meant, nanoparticule
size of an
active agent within the electrospun fiber.
The polymeric carriers may also act as surface modifiers for the
nanoparticulate
drug. However, a second oligomeric surface modifier may also be added to the
electrospinning solution. All of these surface modifiers may physically adsorb
to the
surface of the drug nanoparticles, so as to prevent them agglomerating.
Representative examples of these second oligomeric surface modifier or
excipients,
include but are not limited to: Pluronics~ (block copolymers of ethylene oxide
and
propylene oxide), lecithin, Aerosol OTTM (sodium dioctyl sulfosuccinate),
sodium
lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, i.e., the
polysorbates such
as TweenTM, such as Tween 20, 60 & 80, the sorbitan fatty acid esters, i.e.,
sorbitan
monolaurate, monooleate, monopalmitate, monosterate, etc. such as Span TM or
ArlacelTM, EmsorbTM, CapmulTM, or SorbesterTM, Triton X-200, polyethylene
glycols, glyceryl monostearate, Vitamin E-TPGSTM (d-alpha-tocopheryl
polyethylene
glycol 1000 succinate), sucrose fatty acid esters, such as sucrose stearate,
sucrose
oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate, etc.
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Surfactants are added on a weight/weight basis to the drug composition.
Suitably,
the surfactants are added in amounts of about 10%, preferably about 5% or
less.
Surfactants can lower the viscosity and surface tension of the formulation,
and in
higher amounts can adversely effect the quality of the electrospun fibers.
The surfactant selection may be guided by HLB values but is not necessarily a
useful
criteria. While HLB surfactants have been utilized herein, such as TweenTM 80
(HLB=10), Pluronic F68 (HLB =28), and SDS (HLB>40), lower HLB value
surfactants, such as Pluronic F92 may also be used.
Another pharmaceutically acceptable excipients may be added to the
electrospinning
composition. These excipients may be generally classified as absorption
enhancers;
additional surfactants, flavouring agents, dyes, etc.
Suitable flavoring agents for use herein include, but are not limited to,
wintergreen;
orange, grapefruit, and cherry-raspberry: While w/w% will vary for each
composition, the flavouring agent should be present from about 0.25 to about
5%
w/w of the total formulation.
Suitable coloring agents, pigments, or dyes, such as FD&C or D&C approved
lakes
and dyes, iron oxide and titanium dioxide may also be included in the
formulations.
The amount of pigment present may be from about 0.1 % to about 2.0% by weight
of
the composition.
Additionally, the formulation may also contain sweeteners such as various
natural sugars,
aspartame, sodium cyclamate and sodium saccharinate; as well as the flavorants
such as
those noted above.
The polymeric carriers or the second oligomeric surface modifiers, if
appropriately
chosen, may themselves act as absorption enhancers, depending on the drug.
Suitable absorption enhancers for use herein, include but are not limited to,
chitosan,
lecithin, lectins, sucrose fatty acid esters such as the ones derived from
stearic acid,
oleic acid, palmitic acid, lauric acid, and Vitamin E-TPGS.
Use of the electrospun composition herein may be by conventional capsule or
tablet
fill. Alternatively, the fibers may be ground, suitably by cryogenic means,
for
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compression into a tablet or capsule, for use by inhalation, or parenteral
administration. The fibers may also be dispersed into an aqueous solution
which
may then be directly administered by inhaled or given orally. The fibers may
also be
cut and processed as a sheet for further administration with agents to form a
polymeric film, which may be quick-dissolving.
Another aspect of the present invention is an alternative electrospinning
process for
making the pharmaceutical compositions described herein. The working examples
herein electrostatically charge the solution whereas the pharmaceutical
composition
may also be ejected from a sprayer onto a receiving surface which is
electrostatically
charged and placed at an appropriate distance from the sprayer. As the
ejectant
travels in the air from the sprayer towards the charged collector, fibers are
.formed.
The collectors can be either a metal screen, or in the form of a moving belt.
. vThe
fibers may be deposited on a moving belt which could be continuously removed
and
taken away for further processing as desired.
In a preferred embodiment of the invention for water insoluble agents, is the
active
nabumetone, electrospun in w/w% ranges from 0 to 82 %, with 200K, 400K; 900K
and 2000K POLYOX, and Tween 80, SDS, Pluronic F68, or TPGS. A preferred
solvent system is water/acetonitrile.
EXAMPLES
The invention will now be described by reference to the following examples
which
are merely illustrative and are not to be construed as a limitation of the
scope of the
present invention. All temperatures are given in degrees centigrade, all
solvents are
highest available purity unless otherwise indicated.
Example 1
Electrospinning of 25% (w/w) Aspirin composition
A stock solution of 2.5% solution of POLYOX WSR N-60KTM (Union Carbide) was
prepared in MilliQTM water by gentle mixing in a shaking water bath. 10
milliliters
(hereinafter "mL" or "ml") of this POLYOX solution was added to a solution of
0.12
grams (hereinafter "g") Acetylsalicylic acid (Sigma) in 0.5 mL acetone. The
contents were thoroughly mixed and 1mL of acetone was added to obtain a clear
solution. This solution was transferred to a 25mL glass vessel having a
0.03millimeter (hereinafter "mm") capillary outlet at the bottom and two
inlets, one
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for applying a positive Helium (He) pressure and the other for introducing the
electrode. The electrode was connected to the positive terminal of a high
voltage
power supply (ModelD-ES30P/M692, Gamma High Voltage Research Inc. FL). The
ground from the high voltage power supply was connected to a rotating drum
covered with aluminum foil. The inlet Helium pressure was at 2.5psi and a
voltage
of +14.5KV was applied to the solution. The dry fibers were collected on a
drum
rotating a speed of 50-60 rpm. The fibers were peeled off the drum.
The electrospinning process is further described in J. Doshi's Dissertation,
of "The
ElectroSpinning Process and Applications of Electrospun Fibers", August 1994,
University of Akron, which is incorporated herein by reference in its
entirety.
.. , . . ., , , , .,., .,
. . Example 2
Electrospinning-of 25% Nabumetone composition
.
A stock solution of 30% Polyethylene oxide ( Molecular weight 400K, Aldrich)
was
prepared in MilIiQTM water by: gentle shaking. 5mL of this 30% solution was
added
to 0.5g nabumetone (SB Corporation) dissolved in 6m1 of acetonitrile. The
contents
were gently stirred and another 5mL acetonitrile was added in small portions
until a
cleax solution was obtained. O.lml of TweenTM 80 (Sigma) was added to the
solution. This solution was electrospun using the same conditions described
above
in Example 1. Fibers were collected and removed from the drum.
Example 3
Electrospinning of 30% Nabumetone composition
A stock solution of 7.5% (wlv) POLYOXO WSR N-3000 (Molecular weight of
approx. 400K, Union Caxbide) in MilIiQTM waterlacetonitrile was prepaxed by
mixing 15g of PEO in 50m1 water and 150mL acetonitrile.
To lOmL of this solution was added 0.4g nabumetone along with 1mL acetonitrile
and 0.2mL TweenTM 80 to obtain a homogeneous solution. This solution was
electrospun under the same conditions as described above in example 1 to yield
1.3g
fibers.
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Example 4
Electrospinning of 50% Nabumetone composition
To lOmL of the stock solution of water/acetonitrile from Example 3 above was
added 0.8g nabumetone. The solution was homogenized by adding 1mL acetonitrile
along with 0.2mL TweenTM 80. The solution was spun using similar conditions to
Example 1 above, but using a feed pressure of 2psi and 16KV to yield 1.2g of
fibers.
Example 5
Electrospinning of 70% Nabumetone composition
To 5mL of the POLYOX°.N-3000 solution from Example 3 was added
0.86g of
nabumetone. The solutiom. was made homogeneous by adding 1.6mL of acetonitrile
along with O.lmL T.weenTM 80. The solution was spun using similar conditions
to
Example 1 above, but using a feed pressure of 0.5psi and 16KV to yield 0.93g
of
fibers. . .
Example 6
Electrospinning of 80% Nabumetone composition
To a mixture of 2g Nabumetone, O.lg SDS (JT Baker) and 0.4g
POLYOX° WSR-
1105 (900K) was added 1.2 mL MilliQ° water and 10.5 mL acetonitrile.
This
mixture was left in a shaking water bath at 37°C until all solid
material dissolves to
form a viscous solution. The resultant solution was electrospun using
conditions
similar to Example 1 above, but using a feed pressure of 2 psi and 18KV to
yield
2.1 g of fibers.
Example 7
Electrospinning of 80% Nabumetone composition
To a mixture of 2g Nabumetone, 0.05g Pluronic° F68 (BASF) and 0.4g
POLYOX °
WSR-1105 (900K) was added 1 mL MilliQ° water and 12 mL
acetonitrile. This
mixture was left in a shaking water bath at 37°C until all solid
material dissolves to
form a viscous solution. The resultant solution was electrospun using
conditions
similar to Example 1 above, but using a feed pressure of 2 psi and 18KV to
yield
2.1 g of fibers.
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Example 8
Electrospinning of 80% Nabumetone Composition
Two grams of Nabumetone was dissolved in llmL of acetonitrile. To the solution
was added O.lg of Vitamin E-TPGS (Eastman) and 0.4g POLYOX° WSR-1105
(900K). The mixture was left in a shaking water bath at 37°C until all
solid material
dissolves to form a viscous solution. The resultant solution was electrospun
using
conditions similar to Example 1 above, but using a feed pressure of 0.5 psi
and
16KV to yield 2g of fibers.
Example 9
Determination: of Nabumetone content in the nanofiber composition
Accurately weighed out 20 to 50mg (depending on the expected drug content) of
a
nanofiber composition, such as described above, into a scintillation vial and
dissolved it 5mL acetonitrile/water (80/20) mixture. The solution was
quantitatively v . .
transferred to a 50mL volumetric flask using acetonitrile/water (80/20) and
made up
to volume (50mL) using acetonitrile/water as diluent. Three different samples
taken
from differentparts of fibrous sheets were prepared to determine the
macroscopic
heterogeneity within the fibers.
A standard solution of nabumetone was prepared using accurately weighed sample
of 20mg nabumetone in a 100mL volumetric flask. The sample was made up using
acetonitrile/water(80:20) as a diluent. 20uL of this solution was injected in
Waters
HPLC system equipped with Waters 550 pumps, 717p1us autosampler, and
Spectroflow 783 UV detector. The data acquisition was carried out through a PE
Nelson Box and Turbochrom (PE) software. The mobile phase consisted of
acetonitrile/water/acetic acid in the volume ratio of 44/55/1. The flow rate
was
1.4m1/min and the detection was done at 254nm.
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Nabumetone
Content
(wt. 70)
Sam 1e #1 sam 1e#2 Sam 1e #3
Exam 1e 8 81.2 79.5 81.2
Exam 1e 6 82.9 82.8 83.0
Exam 1e 5 59 61.2 60.8
Exam 1e 4 36 36.9 35
Exam 1e 3 30 ' 30.5 29.8
Example 10
Residual Solvent Analysis in the Nabumetone nanofibers
Residual' solvent'analysis was carried out at QTI (Whitehouse, NJ) using
samples
dissolved in DMSO (dimethyl sulfoxide) and quantitated by capillary Gas
Chromatography: The results, shown in the Table below demonstrate that all the
samples analyzed contained less 100ppm of acetonitrile.
Table
acetonitrile content
Exam 1e 5 <100 m
Exam 1e 4 < 100 m
Exam 1e 3 < 100pp~
Example 11
In-Vitro dissolution Assay
The equipment used for this procedure is a modified USP4, the major
differences
being: 1) low volume cell; 2)stirred cell; 3) retaining filters which are
adequate at
retaining sub micron material. The total run time is 20 minutes. with 2.5mg of
drug
(weigh proportionally more formulated material).
Flow Cell Description: Swinnex filter assemblies obtained from Millipore,
having
0.2 micron Cellulose Nitrate membranes. (Millipore, MA) as internal filters.
The
internal volume of the cell is approximately 2 mL. A Small PTFE stirrer
customized
to fit the Swinnex assembly (Radleys Lab Equipment Halfround Spinvane F37136)
is used. The dissolution medium is water at a flow rate of 5mL/min. The whole
set
up is placed at a thermostat of 37°C. The drug concentration is
measured by passing
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the elutent through a UV detector having a flow cell dimension of lOmm. The UV
detection is carried out at 284nm.
Determination of extent of drug solubility
The experimentation is designed to evaluate drug dissolution rate. As such it
is
unlikely with poorly soluble drugs and with water as the dissolution medium
that
100% of the drug will dissolve in the 20 minute duration of the test. To
determine
the extent of drug solubility over this period collect all 100m1 of solution
that elutes
from the dissolution cell. Using a conventional UV spectrophotometer compare
this
solution against a reference solution of 2.5mg of active agent, for instance
Nabumetone, dissolved in 50/50 methanol/water. (For Nabumetone this can be
prepared by 10 fold dilution of a solution containing 25mg Nabumetone in
100m1s
of 50/50 methanol/water). A suitable wavelength for comparison is 260nm.
~ Example 12
Determination of thermal behavior of nabumetone containing nanofibers.
Thermal studies on nabumetone nanofibers were performed on a MDSC TA
(Wilmington, DE). The samples were heated from 0 to 120°C at
2°C/min at a
modulation frequency of ~0.159°C every 30 seconds. The nanofibers
containing
nabumetone two distinct endotherms at 50°C and 75°C
corresponding to the melting
of POLYOX and nabumetone respectively, when the nabumetone content is above
30% (wt.), below which only one melting endotherm is visible either due to the
formation of a eutectic mixture or because the endotherms overlap.
NabumetoneMelting of Melting of
content POLYOX Nabumetone
(wt.%) C and ~H C and OH
Exam !e 81.2 49.4(22.2 J/ ) 75(80J/ )
8
Exam !e 84.4 51.5 (22.4 J/ 75.3 (82.4J/
7 ) )
Exam !e 82.9 50.5 ( 19.6J1 75.3 (87.3J1
6 ) )
Exam !e 60.3 49.2 (87.4 J/ 69 (86.2J/ )
5 )
Exam !e 35.9 45.1 (69.1J/ ) 59 (7.39J/ )
4
Exam !e 30.1 47 (101J/ )
3
Exam !e 29.3 48 (94.5J/ )
2
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Example 13
Electrospinning of 40% cis-4-Cyano-4-[3-cyclopentyloxyl)-4
methoxyphenyl]cyclohexanecarboxylic acid composition
To lOml of the POLYOX WSRN-3000 solution from Example 3 was added 0.5g of
cis-4-Cyano-4-[3-cyclopentyloxyl)-4-methoxyphenyl]cyclohexanecarboxylic acid
along with 1mL acetonitrile and O.lmL TweenTM 80 to obtain a homogeneous
solution. This solution was electrospun under the same conditions as described
above in Example 1 to yield nanofibers containing the title compound.
Example 14
Electrospinning of (S)-3-Hydroxy-2-phenyl-N-(1-phenylpropyl)-4
quinolinecarboxamide Compositions
Four Hundred milligrams of (S)-3-Hydroxy-2-phenyl-N-(1-phenylpropyl)-4-
quinolinecarboxamide was dissolved~~in 5mL of tetrahydrofuran (G.T Baker). To
this solution 450mg of POLYOX° WSR-1105 (900K) and 50mg Vitamin E=
TPGS(Eastman) were added. The mixture was left in a shaking water bath at
37°C
until all solid material dissolves to form a viscous solution. The viscosity
of the
solution was reduced by added 5mL of acetonitrile. The resultant solution was
electrospun using conditions similar to Example 1 above, but using a feed
pressure
of 0.5 psi and 16 KV to yield 0.5g of fibers.
Example 15
Electrospinning of 4-[2,-(Dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one
monohydrochloride
Two hundred milligrams of Ropirinole was dissolved in 15m1 of milliQ water. To
this solution was added 1g of POLYOX° WSR N3000 NF and 50mg of Tween
80.
The mixture was left shaking in a water bath at 37 °C until all solid
material
dissolved to form a clear viscous solution. This solution was electrospun
using a
conditions similar to Example 1, at a feed pressure of 1 psi and 16 KV to
yield 0.8g
of the material.
Example 16
Electrospinning of 4-[2-(Dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one
monohydrochloride
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Three hundred Fifty milligrams of Ropirinole was dissolved in 15m1 of milliQ
water.
To this solution was added 650mg of POLYOX° WSR N3000 NF and 50mg
of
Tween 80. The mixture was left shaking in a water bath at 37 °C until
all solid
material dissolved to form a clear viscous solution. This solution was
electrospun
using a conditions similar to Example 1, at a feed pressure of 1 psi and 16 KV
to
yield 0.7g of the material.
Example 17
Electrospinning of Paroxetine
One hundred milligrams of paroxetine was dissolved in 20m1 of milliQ water. To
this solution was added 800mg of POLYOX° WSR N3000 NF and 50mg of Tween
80. The mixture was left shaking in a water bath at 37 °C until all
solid material
dissolved to form a clear viscous solution. This solution was electrospun
using a
conditions similar to Example 1;. at a.feed pressure of 1 psi and 16 KV to
yield 0.75g
of the material.
v Example 18
Electrospinning of Kytril
Three hundred milligrams of Kytril was dissolved in 15m1 of milliQ water. To
this
solution was added 650mg of POLYOX° WSR N3000 NF and 50mg of Tween 80:
The mixture was left shaking in a water bath at 37 °C until all solid
material
dissolved to form a clear viscous solution. This solution was electrospun
using a
conditions similar to Example 1, at a feed pressure of 1 psi and 16 kV to
yield 0.7g
of the material.
Example 19
Electrospinning of 10% 2,3-Dihydro-5-methyl-N-[6-(2-pyridinylmethoxy)-3
pyridinyl]-6-(trifluoromethyl)-1H-indole-1-caxboxamide composition
Eight Hundred and Fifty milligrams of POLYOX° WSR-1105 (900K) was
dissolved
in 20m1 acetonitrile by shaking overnight in a water bath at 35°C. This
forms a thick
viscous solution. 5m1 of n-methyl pyrrolidone (NMP) and 50mg of Vitamin E
TPGS(Eastman) were added to the solution and stirred. 100mg of the title
compound
dissolved in lml of NMP was added to the polymer solution. The clear solution
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obtained was electrospun under identical conditions to Example 1, to yield
0.5g of
the product.
Example 20
Electrospinning of 20% 2,3-Dihydro-5-methyl-N-[6-(2-pyridinylmethoxy)-3-
pyridinyl]-6-(trifluoromethyl)-1H-indole-1-carboxamide composition
Seven Hundred and Fifty milligrams of POLYOX° WSR-1105 (900K) was
dissolved in 20m1 acetonitrile by shaking overnight in a water bath at
35°C. This
forms a thick viscous solution. 5m1 of n-methyl pyrrolidone (NMP) and 50mg of
Vitamin E-TPGS(Eastman) were added to the solution and stirred. 200mg of the
title
compound dissolved~in lml of NMP was added to the polymer solution. The clear
solution obtained was -electrospun under identical conditions'to Example 1, to
yield
0.7g of the product.
,~. ,. Example 21
Electrospinning of 68% Nabumetone Composition
Three grams of Nabumetone was dissolved in 20mL of acetonitrile. To the
solution
was added 0.25g of Vitamin E-TPGS(Eastman), 0.8g POLYOX WSR-1105 (900K)
and 0.25g Tween 80. The mixture was left in a shaking water bath at
37°C until all
solid material dissolves to form a viscous solution. The resultant solution
was
electrospun using conditions similar to Example 1 above, but using a feed
pressure
of 0.5 psi and 16KV to yield 3.5g of fibers.
All publications, including but not limited to patents and patent
applications,
cited in this specification are herein incorporated by reference as if each
individual
publication were specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
The above description fully discloses the invention including preferred
embodiments thereof. Modifications and improvements of the embodiments
specifically disclosed herein are within the scope of the following claims.
Without
further elaboration, it is believed that one skilled in the are can, using the
preceding
description, utilize the present invention to its fullest extent. Therefore,
the
Examples herein are to be construed as merely illustrative and not a
limitation of the
scope of the present invention in any way. The embodiments of the invention in
which an exclusive property or privilege is claimed are defined as follows.
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