Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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METHOD FOR REMOVING RESIDUAL ORGANIC SOLVENT FROM
MICROPARTICLES
BACKGROUND
[0001] Microparticles are often prepared using a solvent to dissolve the
polymer
which forms the microparticle matrix. Typical solvents for polyesters such as
lactide
and/or glycolide based polymers include a variety of ICH Class I and Class II
solvents, such as chlorinated solvents. Such solvents are regulated and cannot
be
present above certain amounts in formulations for in vivo use. In many
microparticle
production processes, however, residual solvent is difficult to remove.
Accordingly,
a need exists for methods to overcome the problem of residual solvent.
SUMMARY
[0002] Disclosed herein are methods of overcoming the problem of residual
solvent comprising: (a) mixing microparticles with a surfactant in a non-polar
alkane
to provide a dispersion; wherein the microparticles comprise at least 2% by
weight
residual organic solvent; (b) stirring the dispersion; (c) collecting the
microparticles;
(d) rinsing the microparticles; and (e) drying the microparticles.
DETAILED DESCRIPTION
[0003] In this specification and in the claims that follow, reference will be
made to
a number of terms that shall be defined to have the following meanings:
[0004] Throughout this specification, unless the context requires otherwise,
the
word "comprise," or variations such as "comprises" or "comprising," will be
understood to imply the inclusion of a stated integer or step or group of
integers or
steps but not the exclusion of any other integer or step or group of integers
or
steps.
[0005] The singular forms "a," "an" and "the" include plural referents unless
the
context clearly dictates otherwise. Thus, for example, reference to "a
bioactive
agent" includes mixtures of two or more such agents, and the like.
[0006] "Biodegradable" refers to materials that erode to soluble species or
that
degrade under physiologic conditions to smaller units or chemical species that
are,
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themselves, non-toxic (biocompatible) to the subject and capable of being
metabolized, eliminated, or excreted by the subject.
[0007] The term "microparticle" is used herein to refer generally to a variety
of
structures having sizes from about 10 nm to 2000 microns (2 millimeters) and
includes microcapsule, microsphere, nanoparticle, nanocapsule, nanosphere as
well as particles, in general, that are less than about 2000 microns (2
millimeters).
[0008] A "bioactive agent" refers to an agent that has biological activity.
The
biological agent can be used to treat, diagnose, cure, mitigate, prevent
(i.e.,
prophylactically), ameliorate, modulate, or have an otherwise favorable effect
on a
disease, disorder, infection, and the like. Bioactive agents also include
those
substances which affect the structure or function of a subject, or a pro-drug,
which
becomes bioactive or more bioactive after it has been placed in a
predetermined
physiological environment.
[0009] In one aspect, disclosed herein are methods of overcoming the problem
of
residual solvent comprising: (a) mixing microparticles with a surfactant in a
non-
polar alkane to provide a dispersion; wherein the microparticles comprise at
least
2% by weight residual organic solvent; (b) stirring the dispersion; (c)
collecting the
microparticles; (d) rinsing the microparticles; and (e) drying the
microparticles.
[0010] The methods disclosed herein involve suspending microparticles in a non-
polar alkane surfactant solution to remove residual organic solvent from the
microparticles. The organic solvent that is present in the microparticles can
be
residual from a microparticle preparation process, such as an emulsion
process,
wherein an organic solvent can be used as a solvent for the polymer and/or the
bioactive agent or other excipient. The non-polar alkane can be miscible with
the
residual organic solvent, but does not solubilize polymers of the
microparticle.
However, the non-polar alkane acts as a plasticizer and soaks into the
microparticles, which allows for residual organic solvent, such as a
chlorinated
solvent or ethyl acetate, to diffuse into the heptane solution. The
microparticles are
then washed with a surfactant-free non-polar alkane, such as surfactant-free
heptane. The microparticles can also be rinsed with water, or water and a non-
polar
alkane, such as heptane (including surfactant-free heptane), and dried.
[0011] The residual organic solvent can comprise a 01-04 halogenated alkane
(such as, for example, a 01-04 chlorinated alkane), ethyl acetate, or a
combination
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thereof. The residual organic solvent can be any suitable solvent, including
without
limitation methylene chloride, chloroform, carbon tetrachloride, ethylene
dichloride,
ethylene chloride, 2,2,2-trichloroethane, or a mixture thereof.
[0012] The non-polar alkane solution has a plasticizing effect on the
microparticles particularly when the microparticles comprise lactide and/or
glycolide. When lactide or glycolide based microparticles are suspended in
water
(after preparing the microparticles), the stressed organization of polymers
creates a
large microparticle pore structure and increases diffusivity of substances out
of and
into the microparticles. This, in turn, leads to an initial burst of an
encapsulated
substance. The non-polar alkane solution, however, relaxes the internal stress
of
the polymers and therefore reduces water ingress and initial burst. The non-
polar
alkane, such as heptane, can be used to increase or decrease release of an
agent
in the microparticles (modulate release) while also decreasing residual
organic
solvent levels. In some examples, the bioactive agent has slight or partial
solubility
in the non-polar alkane, for example, at least 0.1 mg/mL, or from 0.1 mg/mL to
0.5
mg/mL. In such cases, the burst or release of the bioactive agent from the
microparticle can be accelerated.
[0013] In contrast to existing phase separation techniques, the disclosed
method
does not involve the use of oils such as silicon oils. Silicone oils are often
used in
microparticle phase separation processes. However, silicone oil can be
difficult to
entirely remove, contaminates surfaces, and can be difficult to discard. The
disclosed method also allows for the ability to exchange an ICH Class II
solvent,
such as dichloromethane or ethyl acetate, with a class III solvent, such as
heptane.
Residual non-polar alkane (such as heptane) that may be present in the
microparticles after carrying out the method is not as great of a concern as
residual
dichloromethane or ethyl acetate.
[0014] As briefly discussed above, the disclosed methods comprise first mixing
microparticles with a surfactant solution in a non-polar alkane to provide a
dispersion of microparticles in the non-polar alkane solution. The surfactant
can be
added to the non-polar alkane prior to the addition of the microparticles. The
surfactant functions to disperse the microparticles such that the non-polar
alkane
can effectively soak and/or penetrate the microparticle matrix.
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[0015] A variety of surfactants can be used. Examples of surfactants include
sorbitol monostearate (also known as SPAN), sorbitan monostearate (also known
as SPAN 60), sorbitan monooleate (SPAN 80), polyoxyethylene sorbitan
monooleate (TWEEN 80), all of which are commercially available. It is
understood
and herein contemplated that the surfactant mixture can comprise any one
surfactant or combination of two, three, four or more surfactants. For
example, the
surfactant mixture can comprise sorbitol monostearate and sorbitan
monostearate,
sorbitol monostearate and sorbitan monooleate; sorbitol monostearate and
polyoxyethylene sorbitan monooleate, sorbitan monostearate and sorbitan
monooleate, sorbitan monostearate and polyoxyethylene sorbitan monooleate,
sorbitan monooleate and polyoxyethylene sorbitan monooleate, sorbitol
monostearate, sorbitan monostearate, and sorbitan monooleate, sorbitol
monostearate, sorbitan monostearate, and polyoxyethylene sorbitan monooleate,
or any other combination of the above identified surfactants. The non-polar
alkane
solution can comprise at least 0.5% surfactant, for example from 0.5% to 10%,
0.5% to 8%, 0.5% to 6%, 0.5% to 5%, or 0.5% to 2%.
[0016] The non-polar alkane can be a variety of alkanes having from 1 to 24
carbons. The alkanes can be branched or unbranched, cyclic, or non-cyclic.
Examples include, without limitation, pentane, cyclopentane, hexanes,
cyclohexane, and heptane. "Hexanes" refers to commercially available hexanes,
which includes a variety of isomers of hexane (all having the formula, C6H14),
and is
thus referred to as "hexanes," rather than "hexane."
[0017] Prior to being added the non-polar alkane solution, the microparticles
comprise some amount of residual solvent left over from a production process,
such as an emulsion process. In one aspect, the disclosed methods can be
useful
for microparticles that comprise at least 2% by weight residual organic
solvent, for
example from 2% to 5%. The residual organic solvent can be the solvent used as
the solvent for the polymer during the microparticle production process. The
non-
polar alkane, in contrast, is not a solvent for the polymer from which the
microparticles were formed. The non-polar alkane is also not a solvent for any
bioactive agent or excipient present in the microparticles. After carrying out
the
disclosed methods, residual solvent amounts can be reduced.
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[0018] After being adding the non-polar alkane solution, the dispersion of
microparticles can be stirred for a period of time generally ranging from a 5
minutes
to 4 hours, for example, from 30 minutes to 2 hours. After stirring the
dispersion,
the microparticles can be collected, for example by filtration or by sieve
separation.
Once the microparticles are collected, the microparticles can be rinsed with
surfactant-free non-polar alkane, such as heptane, water, or a combination
thereof,
and dried. The drying step can be carried out using methods known in the art,
such
as spray-drying, air-drying, vacuum filtration, and the like.
[0019] A variety of microparticle production processes utilize one or more
solvents for the polymer from which the microparticles are formed. These
methods
generally include, without limitation, film casting, molding, spray drying and
extrusion, or emulsion or double-emulsion processes. In one aspect, the
disclosed
methods can be particularly useful for microparticles prepared using emulsion
or
double-emulsion techniques. Emulsion methods for preparing microparticles are
discussed in Jeffery, et al., "The preparation and characterisation of
poly(lactide-co-
glycolide) microparticles. I: Oil-In-water emulsion solvent evaporation," Int.
J.
Pharm. 77(2-3):169-175 (1991); Jeffery, et al., "The Preparation and
Characterization of Poly(lactide-co-glycolide) Microparticles. II. The
Entrapment of a
Model Protein using a (Water-in-Oil)-in-Water Emulsion Solvent Evaporation
Technique," Pharm. Res. 10(3):362-368 (1993). Solvent evaporation methods are
discussed Wichert, B. and Rohdewald, P. (1993) J. Microencapsul. 10:195.
Solvent
extraction methods are described in U.S. Patent No. 5,407,609, the entirety of
which is incorporated herein by reference.
[0020] The microparticles can comprise a variety of biocompatible or
biodegradable polymers. The biocompatible polymer can also be a biodegradable
polymer. In one aspect, the biocompatible polymer can be one or more of
polyesters, polyhydroxyalkanoates, polyhydroxybutyrates, polydioxanones,
polyhydroxyvalerates, polyanhydrides, polyorthoesters, polyphosphazenes,
polyphosphates, polyphosphoesters, polydioxanones, polyphosphoesters,
polyphosphates, polyphosphonates, polyphosphates, polyhydroxyalkanoates,
polycarbonates, polyalkylcarbonates, polyorthocarbonates, polyesteramides,
polyamides, polyamines, polypeptides, polyurethanes, polyalkylene alkylates,
polyalkylene oxalates, polyalkylene succinates, polyhydroxy fatty acids,
polyacetals, polycyanoacrylates, polyketals, polyetheresters, polyethers,
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polyalkylene glycols, polyalkylene oxides, polyethylene glycols, polyethylene
oxides, polypeptides, polysaccharides, or polyvinyl pyrrolidones. Other non-
biodegradable but durable and bioacompatible polymers include without
limitation
ethylene-vinyl acetate co-polymer, polytetrafluoroethylene, polypropylene,
polyethylene, and the like. Likewise, other suitable non-biodegradable
polymers
include without limitation silicones and polyurethanes.
[0021] The biocompatible and/or biodegradable polymer can be a poly(lactide),
a
poly(glycolide), a poly(lactide-co-glycolide), a poly(caprolactone), a
poly(orthoester), a poly(phosphazene), a poly(hydroxybutyrate) or a copolymer
containing a poly(hydroxybutarate), a poly(lactide-co-caprolactone), a
polycarbonate, a polyesteramide, a polyanhydride, a poly(dioxanone), a
poly(alkylene alkylate), a copolymer of polyethylene glycol and a
polyorthoester, a
biodegradable polyurethane, a poly(amino acid), a polyamide, a polyesteramide,
a
polyetherester, a polyacetal, a polycyanoacrylate, a
poly(oxyethylene)/poly(oxypropylene) copolymer, polyacetals, polyketals,
polyphosphoesters, polyhydroxyvalerates or a copolymer containing a
polyhydroxyvalerate, polyalkylene oxalates, polyalkylene succinates,
poly(maleic
acid), and copolymers, terpolymers, combinations, or blends thereof.
[0022] The biocompatible or biodegradable polymer can comprise any lactide
residue, including all racemic and stereospecific forms of lactide, including,
but not
limited to, L-lactide, D-lactide, and D,L-lactide, or a mixture thereof.
Useful
polymers comprising lactide include, but are not limited to poly(L-lactide),
poly(D-
lactide), and poly(DL-lactide); and poly(lactide-co-glycolide), including
poly(L-
lactide-co-glycolide), poly(D-lactide-co-glycolide), and poly(DL-lactide-co-
glycolide);
or copolymers, terpolymers, combinations, or blends thereof. Lactide/glycolide
polymers can be conveniently made by melt polymerization through ring opening
of
lactide and glycolide monomers. Additionally, racemic DL-lactide, L-lactide,
and D-
lactide polymers are commercially available. The L-polymers are more
crystalline
and resorb slower than DL- polymers. In addition to copolymers comprising
glycolide and DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide
are
commercially available. Homopolymers of lactide or glycolide are also
commercially
available.
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[0023] When the biodegradable and/or biocompatible polymer is poly(lactide-co-
glycolide), poly(lactide), or poly(glycolide), the amount of lactide and
glycolide in the
polymer can vary. In a further aspect, the biodegradable polymer contains 0 to
100
mole "Yo, 40 to 100 mole "Yo, 50 to 100 mole "Yo, 60 to 100 mole "Yo, 70 to
100 mole "Yo,
or 80 to 100 mole "Yo lactide and from 0 to 100 mole %, 0 to 60 mole %, 10 to
40
mole %, 20 to 40 mole %, or 30 to 40 mole (:)/0 glycolide, wherein the amount
of
lactide and glycolide is 100 mole %. In a further aspect, the biodegradable
polymer
can be poly(lactide), 95:5 poly(lactide-co-glycolide) 85:15 poly(lactide-co-
glycolide),
75:25 poly(lactide-co-glycolide), 65:35 poly(lactide-co-glycolide), or 50:50
poly(lactide-co-glycolide), where the ratios are mole ratios.
[0024] The biodegradable and/or biocompatible polymer can also be a
poly(caprolactone) or a poly(lactide-co-caprolactone). The polymer can be a
poly(lactide-caprolactone), which, in various aspects, can be 95:5
poly(lactide-co-
caprolactone), 85:15 poly(lactide-co-caprolactone), 75:25 poly(lactide-co-
caprolactone), 65:35 poly(lactide-co- caprolactone), or 50:50 poly(lactide-co-
caprolactone), where the ratios are mole ratios.
[0025] A variety of bioactive agents or other excipients can be present in
the
microparticles. The bioactive agents disclosed herein can be water soluble or
have
at least partial solubility in the non-polar alkanes disclosed herein.
[0026] Examples include without limitation small molecules, peptides,
oligopeptides (e.g., octreotide), proteins such as hormones, enzymes,
antibodies,
receptor binding proteins, antibody fragments, antibody conjugates, nucleic
acids
such as aptamers, iRNA, siRNA, microRNA, DNA, RNA, antisense nucleic acid or
the like, antisense nucleic acid analogs or the like, VEGF inhibitors,
macrocyclic
lactones,dopamine agonists, dopamine antagonists, low-molecular weight
compounds, high-molecular-weight compounds, or conjugated bioactive agents.
[0027] Other bioactive agents can include anabolic agents, antacids, anti-
asthmatic agents, anti-cholesterolemic and anti-lipid agents, anti-coagulants,
anti-
convulsants, anti-diarrheals, anti-emetics, anti-infective agents including
antibacterial and antimicrobial agents, anti-inflammatory agents, anti-manic
agents,
antimetabolite agents, anti-nauseants, anti-neoplastic agents, anti-obesity
agents,
antipsychotics, anti-pyretic and analgesic agents, anti-spasmodic agents, anti-
thrombotic agents, anti-tussive agents, anti-uricemic agents, anti-anginal
agents,
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antihistamines, appetite suppressants, biologicals, cerebral dilators,
coronary
dilators, bronchiodilators, cytotoxic agents, decongestants, diuretics,
diagnostic
agents, erythropoietic agents, expectorants, gastrointestinal sedatives,
hyperglycemic agents, hypnotics, hypoglycemic agents, immunomodulating agents,
ion exchange resins, laxatives, mineral supplements, mucolytic agents,
neuromuscular drugs, peripheral vasodilators, psychotropics, sedatives,
stimulants,
thyroid and anti-thyroid agents, tissue growth agents, uterine relaxants,
vitamins, or
antigenic materials.
[0028] Still other bioactive agents include androgen inhibitors,
polysaccharides,
growth factors, hormones, anti-angiogenesis factors, dextromethorphan,
dextromethorphan hydrobromide, noscapine, carbetapentane citrate,
chlophedianol
hydrochloride, chlorpheniramine maleate, phenindamine tartrate, pyrilamine
maleate, doxylamine succinate, phenyltoloxamine citrate, phenylephrine
hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine
hydrochloride, ephedrine, codeine phosphate, codeine sulfate morphine, mineral
supplements, cholestryramine, N-acetylprocainamide, acetaminophen, aspirin,
ibuprofen, phenyl propanolamine hydrochloride, caffeine, guaifenesin, aluminum
hydroxide, magnesium hydroxide, peptides, polypeptides, proteins, amino acids,
hormones, interferons, cytokines, and vaccines.
[0029] Representative drugs that can be used as bioactive agents include,
but
are not limited to, peptide drugs, protein drugs, therapeutic antibodies,
anticalins,
desensitizing materials, antigens, anti-infective agents such as antibiotics,
antimicrobial agents, antiviral, antibacterial, antiparasitic, antifungal
substances and
combination thereof, antiallergenics, androgenic steroids, decongestants,
hypnotics, steroidal anti-inflammatory agents, anti-cholinergics,
sympathomimetics,
sedatives, miotics, psychic energizers, tranquilizers, vaccines, estrogens,
progestational agents, humoral agents, prostaglandins, analgesics,
antispasmodics, antimalarials, antihistamines, cardioactive agents, anti-
inflammatory agents, nonsteroidal anti-inflammatory agents, antiparkinsonian
agents, antihypertensive agents, 8-adrenergic blocking agents, nutritional
agents,
anti-TNF agents and the benzophenanthridine alkaloids. The agent can further
be a
substance capable of acting as a stimulant, sedative, hypnotic, analgesic,
anticonvulsant, and the like.
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[0030] Other bioactive agents include but are not limited to analgesics
such as
acetaminophen, acetylsalicylic acid, and the like; anesthetics such as
lidocaine,
xylocaine, and the like; anorexics such as dexadrine, phendimetrazine
tartrate, and
the like; antiarthritics such as methylprednisolone, ibuprofen, and the like;
antiasthmatics such as terbutaline sulfate, theophylline, ephedrine, and the
like;
antibiotics such as sulfisoxazole, penicillin G, ampicillin, cephalosporins,
amikacin,
gentamicin, tetracyclines, chloramphenicol, erythromycin, clindamycin,
isoniazid,
rifampin, and the like; antifungals such as amphotericin B, nystatin,
ketoconazole,
and the like; antivirals such as acyclovir, amantadine, and the like;
anticancer
agents such as cyclophosphamide, methotrexate, etretinate, and the like;
anticoagulants such as heparin, warfarin, and the like; anticonvulsants such
as
phenytoin sodium, diazepam, and the like; antidepressants such as
isocarboxazid,
amoxapine, and the like;antihistamines such as diphenhydramine HCI,
chlorpheniramine maleate, and the like; antipsychotics such as clozapine,
haloperidol, carbamazepine, gabapentin, topimarate, bupropion, sertraline,
alprazolam, buspirone, risperidone, aripiprazole, olanzapine, quetiapine,
ziprasidone, iloperidone, and the like; hormones such as insulin, progestins,
estrogens, corticoids, glucocorticoids, androgens, and the like; tranquilizers
such as
thorazine, diazepam, chlorpromazine HCI, reserpine, chlordiazepoxide HCI, and
the
like; antispasmodics such as belladonna alkaloids, dicyclomine hydrochloride,
and
the like; vitamins and minerals such as essential amino acids, calcium, iron,
potassium, zinc, vitamin B12, and the like; cardiovascular agents such as
prazosin
HCI, nitroglycerin, propranolol HCI, hydralazine HCI, pancrelipase, succinic
acid
dehydrogenase, and the like; peptides and proteins such as LHRH, somatostatin,
calcitonin, growth hormone, glucagon-like peptides, growth releasing factor,
angiotensin, FSH, EGF, bone morphogenic protein (BMP), erythopoeitin (EPO),
interferon, interleukin, collagen, fibrinogen, insulin, Factor VIII, Factor
IX, Enbrel ,
Rituxan , Herceptin , alpha-glucosidase, Cerazyme/Ceredose , vasopressin,
ACTH, human serum albumin, gamma globulin, structural proteins, blood product
proteins, complex proteins, enzymes, antibodies, monoclonal antibodies, and
the
like; prostaglandins; nucleic acids; carbohydrates; fats; narcotics such as
morphine,
codeine, and the like, psychotherapeutics; anti-malarials, L-dopa, diuretics
such as
furosemide, spironolactone, and the like; antiulcer drugs such as rantidine
HCI,
cimetidine HCI, and the like.
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[0031] The bioactive agent can also be an immunomodulator, including, for
example, cytokines, interleukins, interferon, colony stimulating factor, tumor
necrosis factor, and the like; allergens such as cat dander, birch pollen,
house dust
mite, grass pollen, and the like; antigens of bacterial organisms such as
Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus,
Streptococcus pyrogenes, Corynebacterium diphteriae, Listeria monocytogenes,
Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium
perfringens. Neisseria meningitides, Neisseria gonorrhoeae, Streptococcus
mutans.
Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae,
Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio
cholerae,
Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae,
Treponema pallidum, Leptspirosis interrogans, Borrelia burgddorferi,
Campylobacter jejuni, and the like; antigens of such viruses as smallpox,
influenza
A and B, respiratory synctial, parainfluenza, measles, HIV, SARS, varicella-
zoster,
herpes simplex 1 and 2, cytomeglavirus, Epstein-Barr, rotavirus, rhinovirus,
adenovirus, papillomavirus, poliovirus, mumps, rabies, rubella,
coxsackieviruses,
equine encephalitis, Japanese encephalitis, yellow fever, Rift Valley fever,
lymphocytic choriomeningitis, hepatitis B, and the like; antigens of such
fungal,
protozoan, and parasitic organisms such as Cryptococcuc neoformans,
Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia
asteroids,
Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamyda
psittaci,
Chlamydia trachomatis, Plasmodium falciparum, Trypanasoma brucei, Entamoeba
histolytica, Toxoplasma gondii, Trichomonas vaginalis, Schistosoma mansoni,
and
the like. These antigens can be in the form of whole killed organisms,
peptides,
proteins, glycoproteins, carbohydrates, or combinations thereof.
[0032] In a further specific aspect, the bioactive agent can comprise an
antibiotic.
The antibiotic can be, for example, one or more of Amikacin, Gentamicin,
Kanamycin, Neomycin, Netilmicin, Streptomycin, Tobramycin, Paromomycin,
Ansamycins, Geldanamycin, Herbimycin, Carbacephem, Loracarbef,
Carbapenems, Ertapenem, Doripenem, Imipenem/Cilastatin, Meropenem,
Cephalosporins (First generation), Cefadroxil, Cefazolin, Cefalotin or
Cefalothin,
Cefalexin, Cephalosporins (Second generation), Cefaclor, Cefamandole,
Cefoxitin,
Cefprozil, Cefuroxime, Cephalosporins (Third generation), Cefixime, Cefdinir,
Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten,
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Ceftizoxime, Ceftriaxone, Cephalosporins (Fourth generation), Cefepime,
Cephalosporins (Fifth generation), Ceftobiprole, Glycopeptides, Teicoplanin,
Vancomycin, Macrolides, Azithromycin, Clarithromycin, Dirithromycin,
Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, Spectinomycin,
Monobactams, Aztreonam, Penicillins, Amoxicillin, Ampicillin, Azlocillin,
Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin,
Meticillin, Nafcillin,
Oxacillin, Penicillin, Piperacillin, Ticarcillin, Polypeptides, Bacitracin,
Colistin,
Polymyxin B, Quinolones, Ciprofloxacin, Enoxacin, Gatifloxacin, Levofloxacin,
Lomefloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Trovafloxacin,
Sulfonamides,
Mafenide, Prontosil (archaic), Sulfacetamide, Sulfamethizole, Sulfanilimide
(archaic), Sulfasalazine, Sulfisoxazole, Trimethoprim, Trimethoprim-
Sulfamethoxazole (Co-trimoxazole) (TMP-SMX), Tetracyclines, including
Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline, and
others; Arsphenamine, Chloramphenicol, Clindamycin, Lincomycin, Ethambutol,
Fosfomycin, Fusidic acid, Furazolidone, Isoniazid, Linezolid, Metronidazole,
Mupirocin, Nitrofurantoin, Platensimycin, Pyrazinamide,
Quinupristin/Dalfopristin,
Rifampicin (Rifampin in U.S.), Tinidazole, Ropinerole, Ivermectin, Moxidectin,
Afamelanotide, Cilengitide, or a combination thereof. In one aspect, the
bioactive
agent can be a combination of Rifampicin (Rifampin in U.S.) and Minocycline.
EXAMPLES
[0033] The following examples are put forth so as to provide those of ordinary
skill in the art with a complete disclosure and description of how the
compounds,
compositions, articles, devices and/or methods claimed herein are made and
evaluated, and are intended to be purely exemplary of the invention and are
not
intended to limit the scope of what the inventors regard as their invention.
Efforts
have been made to ensure accuracy with respect to numbers (e.g., amounts,
temperature, etc.), but some errors and deviations should be accounted for.
Unless
indicated otherwise, parts are parts by weight, temperature is in C or is at
ambient
temperature, and pressure is at or near atmospheric.
Example 1
[0034] Precipitated microparticles were prepared using an emulsion method. The
microparticles were dried and subsequently treated with heptane to remove
residual dichloromethane (DCM). The results are shown in Table 1. 1 h heptane
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treated microparticle refers to the duration that the microparticle was washed
in
heptane.
[0035] Table 1.
Residual
24h In Vitro Residual Heptane
Microparticle Release, % DCM, wt%
Content, wt%
5.60 0.13
Dried microparticle (RSD = 3.23 NA
2.28%)
2.50 0.01
Post dry 1 h heptane treated
(RSD = 2.88 0.02
microparticle
0.41%)
Example 2
[0036] Precipitated microparticles were prepared using an emulsion method.
Without drying, the wet microparticles were treated with heptane to remove
residual
dichloromethane. The results are shown in Table 2. 0.5 h heptane treated
microparticle refers to the duration that the microparticle was washed in
heptane.
[0037] Table 2.
Residual
24h In Vitro Residual Heptane
Microparticle Release, % DCM, wt%
Content, wt%
5.47 0.04
Wet microparticle (RSD = 2.78 NA
0.67%)
3.32 0.13
Post wet 0.5h heptane
treated microparticle (RSD = 2.82 None
detected
Example 3
[0038] Precipitated microparticles were prepared using an emulsion method. The
microparticles were dried and subsequently treated with heptane to remove
residual dichloromethane. The results are shown in Table 3. 2h and 4h heptane
treated microparticles refers to the duration that the microparticle was
washed in
heptane.
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[0039] Table 3.
Residual
24h In Vitro Residual Heptane
Microparticle Release, % DCM, wt% Content, wt%
2.06 0.00
Dry microparticle (RSD = 3.27 NA
0.24%)
0.75 0.04
Post dry 2h heptane treated
(RSD = 2.86 0.12
microparticle
4.84%)
0.72 0.02
Post dry 4h heptane treated
(RSD = 2.89 0.11
microparticle
2.92%)
Example 4
[0040] Precipitated microparticles were prepared using an emulsion method. The
microparticles were dried and subsequently treated with heptane to remove
residual dichloromethane. The results are shown in Table 1. 2h heptane treated
microparticle refers to the duration that the microparticle was washed in
heptane.
[0041] Table 4.
24h In Vitro Residual Residual
Microparticle Release, % DCM, wt% Heptane, wt%
46.59 0.09
Dry microparticle 0.37 <0.1
(RSD = 0.19%)
Post dry 2h heptane 63.97 0.23
<0.1 0.49
treated microparticle (RSD = 0.36%)
Example 5
[0042] Precipitated microparticles were prepared using an emulsion method. The
microparticles were dried and subsequently treated with heptane to remove
residual dichloromethane. The results are shown in Table 2. 2h heptane treated
microparticle refers to the duration that the microparticle was washed in
heptane.
[0043] Table 5.
24h In Vitro Residual Residual
Microparticle Release, % DCM, wt% Heptane, wt%
46.62 0.63
Dry microparticle 1.15 <0.1
(RSD = 1.35%)
Post dry 2h heptane 59.47 0.44
0.39 0.11
treated microparticle (RSD = 0.74%)
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Example 6
[0044] Precipitated microparticles were prepared using an emulsion method. The
microparticles were dried and subsequently treated with heptane to remove
residual dichloromethane. The results are shown in Table 3. 2h heptane treated
microparticle refers to the duration that the microparticle was washed in
heptane.
[0045] Table 6.
24h In Vitro Residual Residual
Microparticle Release, % DCM, wt%
Heptane, wt%
21.57 0.07
Dry microparticle 2.25 <0.1
(RSD = 0.32%)
Post dry 2h heptane 13.53 0.14
1.49 <0.1
treated microparticle (RSD = 1.07%)
[0046] Various modifications and variations can be made to the compounds,
composites, kits, articles, devices, compositions, and methods described
herein.
Other aspects of the compounds, composites, kits, articles, devices,
compositions,
and methods described herein will be apparent from consideration of the
specification and practice of the compounds, composites, kits, articles,
devices,
compositions, and methods disclosed herein. It is intended that the
specification
and examples be considered as exemplary.
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