U.S. patent application number 13/620570 was filed with the patent office on 2013-01-10 for controlled release nanoparticulate compositions.
This patent application is currently assigned to Alkermes Pharma Ireland Limited. Invention is credited to Maurice Joseph Anthony Clancy, Janet Elizabeth Codd, Kenneth Iain Cumming, John G. Devane, Robert Hontz, Rajeev A. Jain, Gary G. Liversidge, Jon Swanson.
Application Number | 20130011447 13/620570 |
Document ID | / |
Family ID | 23321532 |
Filed Date | 2013-01-10 |
United States Patent
Application |
20130011447 |
Kind Code |
A1 |
Swanson; Jon ; et
al. |
January 10, 2013 |
CONTROLLED RELEASE NANOPARTICULATE COMPOSITIONS
Abstract
Described are controlled release nanoparticulate formulations
comprising a nanoparticulate agent to be administered and a
rate-controlling polymer which functions to prolong the release of
the agent following administration. The novel compositions release
the agent following administration for a time period ranging from
about 2 to about 24 hours or longer.
Inventors: |
Swanson; Jon; (North Wales,
PA) ; Jain; Rajeev A.; (Framingham, MA) ;
Hontz; Robert; (Newton Square, PA) ; Devane; John
G.; (Athlone, IE) ; Cumming; Kenneth Iain;
(Essex, GB) ; Clancy; Maurice Joseph Anthony;
(Dublin, IE) ; Codd; Janet Elizabeth; (Athlone,
IE) ; Liversidge; Gary G.; (Charlestown, MA) |
Assignee: |
Alkermes Pharma Ireland
Limited
|
Family ID: |
23321532 |
Appl. No.: |
13/620570 |
Filed: |
September 14, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09337675 |
Jun 22, 1999 |
8293277 |
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13620570 |
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09164351 |
Oct 1, 1998 |
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09337675 |
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Current U.S.
Class: |
424/400 ;
977/773; 977/906 |
Current CPC
Class: |
A61K 9/2077 20130101;
A61K 9/146 20130101; A61P 25/28 20180101; A61P 9/00 20180101; A61K
9/2054 20130101; A61P 3/06 20180101 |
Class at
Publication: |
424/400 ;
977/773; 977/906 |
International
Class: |
A61K 9/14 20060101
A61K009/14 |
Claims
1. A controlled release nanoparticulate composition comprising: (a)
a poorly soluble agent to be administered having an effective
average particle size of less than about 1000 nm; (b) at least one
surface stabilizer associated with the surface of the agent, and
(c) at least one pharmaceutically acceptable rate-controlling
polymer, wherein the composition provides controlled release of the
agent for a time period ranging from about 2 to about 24 hours or
longer.
2.-35. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 09/164,351, filed Oct. 1, 1998. The contents
of that application is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to controlled release
compositions containing a poorly soluble agent such as a drug. In
particular, the present invention relates to compositions in which
the poorly soluble agent is present in nanoparticulate form. The
present invention also relates to solid oral dosage forms
containing such compositions.
BACKGROUND OF THE INVENTION
[0003] Controlled release refers to the release of an agent such as
a drug from a composition or dosage form in which the agent is
released according to a desired profile over an extended period of
time. Controlled release profiles include, for example, sustained
release, prolonged release, pulsatile release, and delayed release
profiles. In contrast to immediate release compositions, controlled
release compositions allow delivery of an agent to a subject over
an extended period of time according to a predetermined profile.
Such release rates can provide therapeutically effective levels of
agent for an extended period of time and thereby provide a longer
period of pharmacologic or diagnostic response as compared to
conventional rapid release dosage forms. Such longer periods of
response provide for many inherent benefits that are not achieved
with the corresponding short acting, immediate release
preparations. For example, in the treatment of chronic pain,
controlled release formulations are often highly preferred over
conventional short-acting formulations.
[0004] Controlled release pharmaceutical compositions and dosage
forms are designed to improve the delivery profile of agents, such
as drugs, medicaments, active agents, diagnostic agents, or any
substance to be internally administered to an animal, including
humans. A controlled release composition is typically used to
improve the effects of administered substances by optimizing the
kinetics of delivery, thereby increasing bioavailability,
convenience, and patient compliance, as well as minimizing side
effects associated with inappropriate immediate release rates such
as a high initial release rate and, if undesired, uneven blood or
tissue levels.
[0005] The term bioavailability is used to describe the degree to
which a drug becomes available at the site(s) of action after
administration. The degree and timing in which an agent such as a
drug becomes available to the target site(s) after administration
is determined by many factors, including the dosage form and
various properties, e.g., dissolution rate of the drug. It is well
known that some drug compositions suffer from poor bioavailability
because of poor solubility of the active ingredient itself.
[0006] Numerous methods have been developed for enhancing the
bioavailability of poorly soluble drugs. Particle size reduction,
such as nanoparticulate forms of the agent, is one such method
since the dissolution rate of a compound is related to the particle
size. Nanoparticulate compositions comprise poorly water-soluble
drug or agent particles having an extremely small particle size,
i.e., less than one micron. With a decrease in particle size, and a
consequent increase in surface area, a composition tends to be
rapidly dissolved and absorbed following administration. For
certain formulations, this characteristic can be highly desirable,
as described, for example, in U.S. Pat. Nos. 5,145,684, 5,510,118,
5,534,270, and 4,826,689, which are specifically incorporated by
reference. However, rapid dissolution is contrary to the goal of
controlled release. Known controlled release formulations do not
present a solution to this problem.
[0007] Prior art teachings of the preparation and use of
compositions providing for controlled release of an active compound
provide various methods of extending the release of a drug
following administration. However, none of the methods suggest a
successful method of administering a nanoparticulate
formulation.
[0008] Exemplary controlled release formulations known in the art
include specially coated pellets, microparticles, implants,
tablets, minitabs, and capsules in which a controlled release of a
drug is brought about, for example, through selective breakdown of
the coating of the preparation, through release through the
coating, through compounding with a special matrix to affect the
release of a drug, or through a combination of these techniques.
Some controlled release formulations provide for pulsatile release
of a single dose of an active compound at predetermined periods
after administration.
[0009] U.S. Pat. No. 5,110,605 to Acharya et al. refers to a
calcium polycarbophil-alginate controlled release composition. U.S.
Pat. No. 5,215,758 to Krishnamurthy et al. refers to a controlled
release suppository composition of sodium alginate and calcium
salt. U.S. Pat. No. 5,811,388 to Friend et al. refers to a solid
alginate-based formulation including alginate, a water-swellable
polymer, and a digestible hydrocarbon derivative for providing
controlled release of orally administered compounds.
[0010] WO 91/13612 refers to the sustained release of
pharmaceuticals using compositions in which the drug is complexed
with an ion-exchange resin. The specific ion-exchange resin
described in this published patent application is AMBERLITE IRP
69.RTM., a sodium polystyrene sulphonate resin.
[0011] U.S. Pat. No. 5,811,425 to Woods et al. refers to injectable
depot forms of controlled release drugs made by forming
microencapsule matrices of the drug in biodegradable polymers,
liposomes, or microemulsions compatible with body tissues. U.S.
Pat. No. 5,811,422 to Lam et al. refers to controlled release
compositions obtained by coupling a class of drugs to biodegradable
polymers, such as polylactic acid, polyglycolic acid, copolymers of
polylactic and polyglycolic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, etc.
[0012] U.S. Pat. No. 5,811,404 to De Frees et al. refers to the use
of liposomes having prolonged circulation half-lives to provide for
the sustained release of drug compositions.
[0013] Nanoparticulate compositions addressed a need in the art for
pharmaceutically-acceptable compositions containing poorly-water
soluble agents. However, the known nanoparticulate compositions are
not suitable for controlled-release formulations. There remains a
need in the art for controlled release nanoparticulate
compositions.
SUMMARY OF THE INVENTION
[0014] This invention is directed to the surprising and unexpected
discovery of new controlled release nanoparticulate compositions.
The controlled release compositions provide for the therapeutically
effective release of an incorporated drug or other substance in a
patient for a time period ranging from about 2 to about 24 hours or
longer.
[0015] The controlled release nanoparticulate compositions comprise
a nanoparticulate drug or other agent to be administered, such as a
crystalline or amorphous nanoparticulate drug or other agent, or a
combination of a crystalline and amorphous nanoparticulate drug or
other agent, having an effective average particle size, prior to
inclusion in the composition, of less than about 1000 nm. The
composition also comprises at least one surface stabilizer
associated with the surface of the nanoparticulate drug or other
agent. In addition, the controlled release nanoparticulate
composition comprises one or more pharmaceutically acceptable
rate-controlling polymers, which function to prolong release of the
administered nanoparticulate drug or agent thereby resulting in
controlled release. Optionally, one or more auxilary excipient
materials can also be included in the controlled release
composition.
[0016] Controlled release compositions according to this invention
containing a nanoparticulate form of a poorly soluble drug are
advantageous in that the improved bioavailability achieved by size
reduction of the drug can be exploited to maintain an effective
blood concentration over an extended period of time after
administration.
[0017] Preferably, the effective average particle size of the
nanoparticulate agent prior to inclusion in the controlled release
nanoparticulate composition is less than about 1000 nm, less than
about 800 nm, less than about 600 nm, less than about 400 nm, less
than about 300 nm, less than about 250 nm, less than about 100 nm,
or less than about 50 nm. Nanoparticulate compositions were first
described in U.S. Pat. No. 5,145,684 ("the '684 patent"), described
above.
[0018] The present invention also provides dosage forms for the
controlled release composition as described above in tablet form or
in multiparticulate form to be administered in any conventional
method, such as via oral, rectal, buccal, and vaginal routes. The
tablet form may be, for instance, coated tablets, multilayer
tablets, matrix tablets, and the like. The multiparticulate form
may be, for instance, particles, pellets, mini-tablets, or the
like.
[0019] In a first aspect of the invention, the nanoparticulate drug
or other agent, at least one surface stabilizer, and one or more
auxiliary excipient materials are compressed into tablet form prior
to coating with a rate controlling polymer material.
[0020] In a second aspect, the nanoparticulate drug or other agent,
at least one surface stabilizer, the rate controlling polymer
material, and one or more auxiliary excipients are compressed
together to form a controlled release matrix. The controlled
release matrix may optionally be coated with a rate controlling
polymer so as to provide additional controlled release
properties.
[0021] In a third aspect, the nanoparticulate drug or other agent,
at least one surface stabilizer, and one or more auxiliary
excipient materials are compressed into the form of a multilayer
tablet prior to coating with a rate controlling polymer
material.
[0022] In a fourth aspect, the nanoparticulate drug or other agent
and at least one surface stabilizer are dispersed in the rate
controlling polymer material and compressed into the form of a
multilayer tablet. The multilayer tablet may optionally be coated
with a rate controlling polymer material so as to provide
additional controlled release properties. In an alternative aspect,
a first layer in such a multilayer tablet comprises a controlled
release composition according to the invention and a second layer
comprises a conventional active ingredient containing composition,
such as an instant release composition.
[0023] In a fifth aspect, the nanoparticulate drug or other agent
and at least one surface stabilizer are incorporated into a single
layer or multilayer tablet containing osmagent surrounded by a
semi-permeable membrane, with the semi-permeable membrane defining
an orifice. In this embodiment the semi-permeable membrane is
permeable to aqueous media, such as gastrointestinal fluids, but it
is not permeable to the poorly soluble drug compound when in
solution or when in other form. Such osmotic delivery systems are
well known in the art, wherein infusion of fluid through the
semi-permeable membrane causes the osmagent to swell thus driving
the drug compound through the orifice defined by the semi-permeable
membrane.
[0024] In a sixth aspect, the nanoparticulate drug or other agent,
at least one surface stabilizer, one or more auxiliary excipients,
and the rate controlling polymer material are combined into a
multiparticulate form. The multiparticulate form preferably
comprises discrete particles, pellets, mini-tablets, or
combinations thereof. In a final oral dosage form the
multiparticulate form may be encapsulated, for example in hard or
soft gelatin capsules. Alternatively, a multiparticulate form may
be incorporated into other final dosage forms such as a sachet. In
the case of a multiparticulate form comprising discrete particles
or pellets, the multiparticulate form may be compressed, optionally
with additional auxiliary excipients, into the form of tablets. The
compressed multiparticulate tablet may optionally be coated with
rate controlling polymer material so as to provide additional
controlled release properties.
[0025] The present invention further relates to processes for the
manufacture of controlled release compositions in which a poorly
soluble drug or other agent is present in nanoparticulate form. In
one aspect, the method comprises: (1) forming a nanoparticulate
composition comprising a poorly soluble drug or other agent to be
administered and a surface stabilizer; (2) adding one or more
pharmaceutically acceptable rate-controlling polymers, and (3)
forming a solid dose form of the composition for administration.
Pharmaceutically acceptable excipients can also be added to the
composition for administration. Methods of making nanoparticulate
compositions, which can comprise mechanical grinding,
precipitation, or any other suitable size reduction process, are
known in the art and are described in, for example, the '684
patent.
[0026] Yet another aspect of the present invention provides a
method of treating a mammal, including a human, requiring extended
administration of a drug or other agent with a controlled release
nanoparticulate composition of the invention which releases an
incorporated drug or other agent providing a desired effect for a
period from about 2 to about 24 hours or longer. The controlled
release nanoparticulate composition can be administered in any
conventional method, such as via oral, rectal, buccal, and vaginal
routes.
[0027] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory and are intended to provide further explanation of
the invention as claimed. Other objects, advantages, and novel
features will be readily apparent to those skilled in the art from
the following detailed description of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0028] FIG. 1: Shows a graph of the cumulative % drug (naproxen)
released over time using a nanoparticulate composition comprising
30% Klucel.RTM. hydroxypropylcellulose (HPC) and 3%
polyvinylpyrrolidone (PVP);
[0029] FIG. 2: Shows a graph of the cumulative % drug (naproxen)
released over time for three different nanoparticulate compositions
having a hardness of 15, 25, and 35 kP;
[0030] FIG. 3: Shows a graph of the cumulative % drug (naproxen)
released over time for nanoparticulate compositions comprising
different types of hydroxypropyl methylcellulose (HPMC);
[0031] FIG. 4: Shows a graph of the cumulative % drug (naproxen)
released over time for nanoparticulate compositions comprising one
of six different types of HPMC;
[0032] FIG. 5: Shows a graph of the cumulative % drug (naproxen)
released over time for nanoparticulate compositions having varying
amounts Lubritab.RTM. (a hydrogenated vegetable oil);
[0033] FIG. 6: Shows a graph comparing the cumulative % drug
(naproxen) released over time for a spray-dried nanoparticulate
formulation and a formulation of blended raw drug and
stabilizer;
[0034] FIG. 7: Shows a graph comparing the cumulative % drug
(naproxen) released over time for nanoparticulate formulations
comprising different concentrations of Methocel.RTM. K100LV
(HPMC);
[0035] FIG. 8: Shows a graph comparing the cumulative % drug
(naproxen) released over time for directly compressed and wet
granulated nanoparticulate formulations of Klucel.RTM. and
Methocel.RTM.; and
[0036] FIG. 9: Shows the controlled release of nanoparticulate
glipizide from directly compressed Methocel.RTM. tablets.
[0037] FIG. 10: Shows the mean in vivo plasma profiles of
nifedipine after single dosed, fasted, administration in humans for
(1) nifedipine containing controlled release matrix tablets coated
with a controlled release coating according to the present
invention as described in Example 12; and (2) a control
composition.
[0038] FIG. 11: Shows the mean in vivo plasma profiles of
nifedipine after single dosed, fasted, administration in humans for
(1) a nifedipine controlled release composition manufactured
according to the present invention as described in Example 14; and
(2) a control composition.
[0039] FIG. 12: Depicts the comparison of the plasma concentration
of nifedipine having a D.sub.90 particle size of 500 nm with that
of nifedipine having a D.sub.90 particle size of 186 .mu.m over a
period of 24 hours after administration.
DETAILED DESCRIPTION OF THE INVENTION
A. Controlled Release Nanoparticulate Compositions
[0040] This invention is directed to the surprising and unexpected
discovery of new solid dose controlled release nanoparticulate
compositions. It is expected that the controlled release
compositions provide effective blood levels of an incorporated
nanoparticulate drug or other agent in a patient for an extended
period of time. Such a discovery was unexpected because the
nanoparticulate size of the drug or other agent, resulting in a
large surface area in relation to the volume, results in rapid
dissolution of the drug or other agent following administration.
Rapid dissolution is seemingly contrary to the goal of controlled
release formulations.
[0041] As used herein, "controlled release" means the release of an
agent such as a drug from a composition or dosage form in which the
agent is released according to a desired profile over an extended
period of time, such as from about 2 to about 24 hours or longer.
Release over a longer time period is also contemplated as a
"controlled release" dosage form of the present invention.
[0042] The solid dose controlled release nanoparticulate
compositions of the invention comprise a crystalline or amorphous
nanoparticulate drug or other agent to be administered, having an
effective average particle size of less than about 1000 nm, at
least one surface stabilizer associated with the surface of the
drug or agent, and, additionally, one or more rate-controlling
polymers. Preferably, the effective average particle size of the
nanoparticulate drug is less than about 800 nm, less than about 600
nm, less than about 400 nm, less than about 300 nm, less than about
250 nm, less than about 100 nm, or less than about 50 nm. The
crystalline form of a drug or other agent is distinguishable from a
non-crystalline or amorphous phase of a drug or other agent.
[0043] 1. Nanoparticulate Compositions
[0044] The starting nanoparticulate composition (prior to addition
of the one or more rate-controlling polymers) comprises a drug or
other agent to be administered and at least one surface stabilizer
associated with the surface of the nanoparticulate drug or
agent.
[0045] a. Agent to be Administered
[0046] The nanoparticles of the invention comprise a therapeutic
agent, diagnostic agent, or other agent to be administered for
controlled release. A therapeutic agent can be a drug or
pharmaceutical, and a diagnostic agent is typically a contrast
agent, such as an x-ray contrast agent, or any other type of
diagnostic material. The drug or diagnostic agent exists as a
discrete, crystalline phase, as an amorphous phase, or as a
combination thereof. The crystalline phase differs from a
non-crystalline or amorphous phase that results from precipitation
techniques, such as those described in EPO 275,796.
[0047] The invention can be practiced with a wide variety of drugs
or diagnostic agents. The drug or diagnostic agent is preferably
present in an essentially pure form, is poorly water soluble, and
is dispersible in at least one liquid medium. By "poorly water
soluble" it is meant that the drug or diagnostic agent has a
solubility in the liquid dispersion medium of less than about 30
mg/ml, preferably less than about 10 mg/ml, and preferably less
than about 1 mg/ml.
[0048] Suitable drugs or diagnostic agents include those intended
for controlled release delivery. Preferable drug classes include
those that have short half-lives for clearance.
[0049] The drug can be selected from a variety of known classes of
drugs, including, for example, analgesics, anti-inflammatory
agents, anthelmintics, anti-arrhythmic agents, antiasthma agents,
antibiotics (including penicillins), anticoagulants,
antidepressants, antidiabetic agents, antiepileptics,
antihistamines, antitussives, antihypertensive agents,
antimuscarinic agents, antimycobacterial agents, antineoplastic
agents, antipyretics, immunosuppressants, immunostimulants,
antithyroid agents, antiviral agents, anxiolytic sedatives
(hypnotics and neuroleptics), astringents, beta-adrenoceptor
blocking agents, blood products and substitutes, bronchodilators,
cardiac inotropic agents, chemotherapeutics, contrast media,
corticosteroids, cough suppressants (expectorants and mucolytics),
diagnostic agents, diagnostic imaging agents, diuretics,
dopaminergics (antiparkinsonian agents), haemostatics,
immunological agents, lipid regulating agents, muscle relaxants,
proteins, polypeptides, parasympathomimetics, parathyroid
calcitonin and biphosphonates, prostaglandins,
radio-pharmaceuticals, hormones, sex hormones (including steroids),
anti-allergic agents, stimulants and anoretics, sympathomimetics,
thyroid agents, vaccines, vasodilators, and xanthines.
[0050] A description of these classes of drugs and diagnostic
agents and a listing of species within each class can be found, for
instance, in Martindale, The Extra Pharmacopoeia, Twenty-ninth
Edition (The Pharmaceutical Press, London, 1989), specifically
incorporated by reference. The drugs or diagnostic agents are
commercially available and/or can be prepared by techniques known
in the art.
[0051] Poorly water soluble drugs which may be suitably used in the
practice of the present invention include but are not limited to
alprazolam, amiodarone, amlodipine, astemizole, atenolol,
azathioprine, azelatine, beclomethasone, budesonide, buprenorphine,
butalbital, carbamazepine, carbidopa, cefotaxime, cephalexin,
cholestyramine, ciprofloxacin, cisapride, cisplatin,
clarithromycin, clonazepam, clozapine, cyclosporin, diazepam,
diclofenac sodium, digoxin, dipyridamole, divalproex, dobutamine,
doxazosin, enalapril, estradiol, etodolac, etoposide, famotidine,
felodipine, fentanyl citrate, fexofenadine, finasteride,
fluconazole, flunisolide, flurbiprofen, fluvoxamine, furosemide,
glipizide, gliburide, ibuprofen, isosorbide dinitrate,
isotretinoin, isradipine, itraconazole, ketoconazole, ketoprofen,
lamotrigine, lansoprazole, loperamide, loratadine, lorazepam,
lovastatin, medroxyprogesterone, mefenamic acid,
methylprednisolone, midazolam, mometasone, nabumetone, naproxen,
nicergoline, nifedipine, norfloxacin, omeprazole, paclitaxel,
phenyloin, piroxicam, quinapril, ramipril, risperidone, sertraline,
simvastatin, terbinafine, terfenadine, triamcinolone, valproic
acid, zolpidem, or pharmaceutically acceptable salts of any of the
abovementioned drugs.
[0052] b. Surface Stabilizers
[0053] Useful surface stabilizers, which are known in the art and
described, for example, in the '684 patent, are believed to include
those which physically adhere to the surface of the drug or agent
but do not chemically bond to or interact with the drug or agent.
The surface stabilizer is associated with the surface of the drug
or agent in an amount sufficient to maintain an effective average
particle size of less than about 1000 nm. Furthermore, the
individual molecules of the surface stabilizer are essentially free
of intermolecular cross-linkages.
[0054] Suitable surface stabilizers can preferably be selected from
known organic and inorganic pharmaceutical excipients. Such
excipients include various polymers, low molecular weight
oligomers, natural products, and surfactants. Preferred surface
stabilizers include nonionic and ionic surfactants.
[0055] Representative examples of surface stabilizers include
gelatin, casein, lecithin (phosphatides), dextran, gum acacia,
cholesterol, tragacanth, stearic acid, benzalkonium chloride,
calcium stearate, glycerol monostearate, cetostearyl alcohol,
cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene
alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000),
polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan
fatty acid esters (e.g., the commercially available Tweens.RTM.
such as e.g., Tween 20.RTM. and Tween 80.RTM. (ICI Specialty
Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550.RTM. and
934.RTM. (Union Carbide)), polyoxyethylene stearates, colloidal
silicon dioxide, phosphates, sodium dodecylsulfate,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose,
magnesium aluminum silicate, triethanolamine, polyvinyl alcohol
(PVA), polyvinylpyrrolidone (PVP),
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde (also known as tyloxapol, superione, and triton),
poloxamers (e.g., Pluronics F68.RTM. and F108.RTM., which are block
copolymers of ethylene oxide and propylene oxide); poloxamines
(e.g., Tetronic 908.RTM., also known as Poloxamine 908.RTM., which
is a tetrafunctional block copolymer derived from sequential
addition of propylene oxide and ethylene oxide to ethylenediamine
(BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508.RTM.
(T-1508) (BASF Wyandotte Corporation), dialkylesters of sodium
sulfosuccinic acid (e.g., Aerosol OT.RTM., which is a dioctyl ester
of sodium sulfosuccinic acid (American Cyanamid)); Duponol P.RTM.,
which is a sodium lauryl sulfate (DuPont); Tritons X-200.RTM.,
which is an alkyl aryl polyether sulfonate (Rohm and Haas);
Crodestas F-110.RTM., which is a mixture of sucrose stearate and
sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol),
also known as Olin-lOG.RTM. or Surfactant 10-G.RTM. (Olin
Chemicals, Stamford, Conn.); Crodestas SL-40.RTM. (Croda, Inc.);
and SA9OHCO, which is
C.sub.18H.sub.37CH.sub.2(CON(CH.sub.3)--CH.sub.2(CHOH).sub.4(CH.sub.2OH).-
sub.2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl
.beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; and the like.
[0056] Most of these surface stabilizers are known pharmaceutical
excipients and are described in detail in the Handbook of
Pharmaceutical Excipients, published jointly by the American
Pharmaceutical Association and The Pharmaceutical Society of Great
Britain (The Pharmaceutical Press, 1986), specifically incorporated
by reference.
[0057] c. Particle Size
[0058] By "an effective average particle size of less than about
1000 nm" it is meant that at least 50% of the drug/agent particles
have an average particle size of less than about 1000 nm when
measured by light scattering techniques. Preferably, at least 70%
of the particles have an average particle size of less than the
effective average, i.e., about 1000 nm, more preferably at least
about 90% of the particles have an average particle size of less
than the effective average.
[0059] As used herein, particle size is determined on the basis of
the weight average particle size as measured by conventional
particle size measuring techniques well known to those skilled in
the art. Such techniques include, for example, sedimentation field
flow fractionation, photon correlation spectroscopy, light
scattering, and disk centrifugation. By "an effective average
particle size of less than about 1000 nm" it is meant that at least
70% of the particles, by weight, have a particle size of less than
about 1000 nm when measured by the above-noted techniques. In
preferred embodiments, the effective average particle size is less
than about 800 nm, less than about 600 nm, less than about 400 nm,
less than about 300 nm, less than about 250 nm, less than about 100
nm, or less than about 50 nm.
[0060] As used herein, the mean diameter of 50% of the particles,
D.sub.v,50 refers to the volume average diameter of 50% of the
particles or the value below which 50% of the particles have an
equivalent volume diameter.
[0061] 2. Rate-Controlling Polymers
[0062] The present invention identifies pharmaceutically acceptable
rate-controlling polymers (also referred to herein as rate
controlling polymer material) that unexpectedly provide excellent
controlled release properties for nanoparticulate compositions.
Rate-controlling polymers include hydrophilic polymers, hydrophobic
polymers, and mixtures of hydrophobic and hydrophilic polymers that
are capable of retarding the release of a drug compound from a
composition or dosage form of the present invention.
[0063] Particularly useful rate-controlling polymers for causing an
effective controlled release of administered drug or agent
following administration include plant exudates (gum arabic),
seaweed extracts (agar), plant seed gums or mucilages (guar gum),
cereal gums (starches), fermentation gums (dextran), animal
products (gelatin), hydroxyalkyl celluloses such as hydroxypropyl
cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl
methylcelluose (HPMC), and sodium carboxymethylcellulose (CMC),
guar, pectin, and carrageenan. Additional polymers include
poly(ethylene)oxide, alkyl cellulose such as ethyl cellulose and
methyl cellulose, carboxymethyl cellulose, hydrophilic cellulose
derivatives, polyethylene glycol, polyvinylpyrrolidone, cellulose
acetate, cellulose acetate butyrate, cellulose acetate phthalate,
cellulose acetate trimellitate, polyvinyl acetate phthalate,
hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl
cellulose acetate succinate, polyvinyl acetaldiethylamino acetate,
poly(alkylmethacrylate) and poly(vinyl acetate). Other suitable
hydrophobic polymers include polymers and/or copolymers derived
from acrylic or methacrylic acid and their respective esters,
waxes, shellac, and hydrogenated vegetable oils. Two or more
rate-controlling polymers can be used in combination. The polymers
are commercially available and/or can be prepared by techniques
known in the art.
[0064] 3. Other Pharmaceutical Excipients
[0065] Pharmaceutical compositions according to the invention may
also comprise one or more auxiliary excipients such as binding
agents, diluents, lubricating agents, plasticisers, anti-tack
agent, opacifying agents, suspending agents, sweeteners, flavoring
agents, preservatives, buffers, wetting agents, disintegrants,
pigments, and other excipients. Such excipients are known in the
art. As will be appreciated by those skilled in the art, the exact
choice of excipients and their relative amounts will depend to some
extent on the dosage form into which the controlled release
composition is incorporated.
[0066] Suitable diluents include for example pharmaceutically
acceptable inert fillers such as microcrystalline cellulose,
lactose, dibasic calcium phosphate, saccharides, and/or mixtures of
any of the foregoing. Examples of diluents include microcrystalline
cellulose such as Avicel pH101, Avicel pH102, and Avicel pH112;
lactose such as lactose monohydrate, lactose anhydrous, and
Pharmatose DCL21; dibasic calcium phosphate such as Emcompress;
mannitol; starch; sorbitol; sucrose; and glucose. The diluent, if
present, is preferably used in an amount of from about 5 mg to
about 800 mg per dosage unit, more preferably from about 10 mg to
about 600 mg per dosage unit and most preferably from about 20 mg
to about 400 mg per dosage unit.
[0067] Examples of binding agents are various celluloses and
cross-linked polyvinylpyrrolidone.
[0068] Suitable lubricants, including agents that act on the
flowability of the powder to be compressed, are colloidal silicon
dioxide, such as Aerosil 200; talc, stearic acid, magnesium
stearate, calcium stearate, stearic acid, and silica gel.
[0069] Examples of sweeteners are any natural or artificial
sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate,
aspartame, and acsulfame. Examples of flavoring agents are
Magnasweet (trademark of MAFCO), bubble gum flavor, and fruit
flavors, and the like.
[0070] Examples of preservatives are potassium sorbate,
methylparaben, propylparaben, benzoic acid and its salts, other
esters of parahydroxybenzoic acid such as butylparaben, alcohols
such as ethyl or benzyl alcohol, phenolic compounds such as phenol,
or quarternary compounds such as benzalkonium chloride.
[0071] Suitable disintegrants include lightly crosslinked polyvinyl
pyrrolidone, corn starch, potato starch, maize starch, and modified
starches, croscarmellose sodium, cross-povidone, sodium starch
glycolate, and mixtures thereof.
[0072] 4. Quantities of Nanoparticulate
[0073] Composition and Rate-Controlling Polymer(s)
[0074] The relative amount of nanoparticulate agent in the
controlled release compositions of the invention can vary widely
and can depend upon, for example, the agent selected for controlled
release delivery. The poorly soluble drug or pharmaceutically
acceptable salt thereof may be present in any amount which is
sufficient to elicit a therapeutic effect and, where applicable,
may be present either substantially in the form of one optically
pure enantiomer or as a mixture, racemic or otherwise, of
enantiomers. The amount of poorly soluble drug compound, or
pharmaceutically acceptable salt thereof, in the controlled release
composition of the present invention is suitably in the range of
from about 1 .mu.g to about 800 mg, preferably in the range of from
about 0.25 mg to about 600 mg and more preferably in the range of
from about 1 mg to about 500 mg.
[0075] The nanoparticulate agent, preferably in combination with
the surface stabilizer, can be present in the controlled release
compositions of the invention in an amount of about 95% to about
5%, preferably about 80% to about 10% by weight based on the total
weight of the dry composition.
[0076] The one or more rate-controlling polymers can be present in
an amount of about 5% to about 95%, preferably about 10% to about
65% by weight based on the total weight of the dry composition.
[0077] 5. Optimization of Other Variables for Increasing Controlled
Release
[0078] Other than selection of the one or more rate-controlling
polymers, hardness of the tablet is the factor which contributes
most to extended controlled release of the administered agent. A
hardness of about 10 kP to about 50 kP is preferred, with a
hardness of about 30 to about 35 kP being most preferred. Factors
such as wet-granulation of the rate-controlling polymer and an
increase in the concentration of the rate-controlling polymer allow
for a more controlled release, while factors such as micronization
of the rate-controlling polymer give a more immediate release of
the administered agent.
B. Methods of Making Controlled Release Nanoparticulate Dosage
Forms
[0079] In another aspect of the invention there is provided a
method of preparing controlled release nanoparticulate
formulations. The method comprises: (1) forming a nanoparticulate
composition comprising an agent to be administered and, preferably,
a surface stabilizer; (2) adding one or more rate-controlling
polymers, and (3) forming a solid dose form of the composition for
administration. Pharmaceutically acceptable excipients can also be
added to the composition for administration. Methods of making
nanoparticulate compositions, which can comprise mechanical
grinding, precipitation, or any other suitable size reduction
process, are known in the art and are described in, for example,
the '684 patent. A redispersing agent or combination of
redispersing agents may be included to facilitate processing of the
nanoparticulate drug.
[0080] Methods for making solid dose pharmaceutical formulations
are known in the art, and such methods can be employed in the
present invention. Exemplary solid dose controlled release
formulations of the invention can be prepared by, for example,
combining the one or more rate-controlling polymers with a raw
nanoparticulate mixture obtained after size reduction of an agent
to be administered. The resultant composition can be formulated
into tablets for oral administration. Alternatively, the one or
more rate-controlling polymers can be combined with a
nanoparticulate dispersion that has been spray dried.
[0081] Oral dosage forms of the controlled release composition
according to the present invention can be in the form of tablets or
can be multiparticulate. The term "tablet" or "tablets" as used
herein includes, but is not limited to, instant release (IR)
tablets, matrix tablets, multilayer tablets, and multilayer matrix
tablets which may be optionally coated with one or more coating
materials. The term "tablet" also includes osmotic delivery systems
in which a drug compound is combined with an osmagent (and
optionally other excipients) and coated with a semi-permeable
membrane, the semi-permeable membrane defining an orifice through
which the drug compound may be released. Tablet oral dosage forms
particularly useful in the practice of the invention include those
selected from the group consisting of coated IR tablets, matrix
tablets, coated matrix tablets, multilayer tablets, coated
multilayer tablets, multilayer matrix tablets, and coated
multilayer matrix tablets. The term "multiparticulate" as used
herein includes discrete particles, pellets, mini-tablets, and
mixtures or combinations thereof. If the oral form is a
multiparticulate capsule, such hard or soft gelatin capsules can
suitably be used to contain the multiparticulate. A
multiparticulate oral dosage form according to the invention may
comprise a blend of two or more populations of particles, pellets,
or mini-tablets having different in vitro and/or in vivo release
characteristics. For example, a multiparticulate oral dosage form
may comprise a blend of an instant release component and a delayed
release component contained in a suitable capsule.
[0082] If desired, the multiparticulate may be coated with a layer
containing controlled release polymer material. Alternatively, the
multiparticulate and one or more auxiliary excipient materials can
be compressed into tablet form such as a multilayer tablet.
Typically, a multilayer tablet may comprise two layers containing
the same or different levels of the same active ingredient having
the same or different release characteristics. Alternatively, a
multilayer tablet may contain different active ingredient in each
layer. Multilayer tablets may optionally be coated with a
controlled release polymer so as to provide additional controlled
release properties.
[0083] In one embodiment of the invention the rate controlling
polymer material is applied as a coating to tablets comprising the
poorly soluble drug compound and any auxiliary excipients which may
be required. The coating may be applied to the tablets by any
suitable technique. Such techniques will be apparent to those
skilled in the art. Particularly useful for application of the
coating is the technique of spray coating, carried out for instance
using a fluidised bed coating apparatus or using a side vented
coating pan. Suitable auxiliary excipients and/or additives may be
added to the coating formulation. For example, it may be desirable
to add plasticisers, glidants, anti-tack agents, pigments, and
other excipients to the coating formulation. The coating may be
applied to the tablets in any amount which is sufficient to give
the desired degree of controlled release.
[0084] In one embodiment a process for the manufacture of a
controlled release composition comprises the steps of: (i) spray
drying a nanoparticulate dispersion of a poorly soluble drug,
optionally in the presence of a surfactant or a surface stabilizer,
to form a redispersible material; (ii) blending the redispersible
material with auxiliary excipients to form a blend, (iii)
compressing the blend into tablets, and (iv) coating the tablets
with a rate controlling polymer material.
[0085] In an another embodiment, a process for the manufacture of a
controlled release composition comprises the steps of: (i) spray
drying a nanoparticulate dispersion of a poorly soluble drug,
optionally in the presence of a surfactant or a surface stabilizer,
to form a redispersible material; (ii) blending the redispersible
material with a rate controlling polymer material and optionally
auxiliary excipients to form a blend, and (iii) compressing the
blend to form tablets. The process may optionally comprise the
additional step of coating the tablets with an additional rate
controlling polymer material.
[0086] 1. Spray Drying of Nanoparticulate Dispersions
[0087] Solid dose forms of nanoparticulate dispersions can be
prepared by drying the nanoparticulate formulation following size
reduction. A preferred drying method is spray drying. The spray
drying process is used to obtain a nanoparticulate powder following
the size reduction process used to transform the drug into
nanoparticulate sized particles. Such a nanoparticulate powder can
be formulated into tablets for oral administration.
[0088] In an exemplary spray drying process, the nanoparticulate
drug suspension is fed to an atomizer using a peristaltic pump and
atomized into a fine spray of droplets. The spray is contacted with
hot air in the drying chamber resulting in the evaporation of
moisture from the droplets. The resulting spray is passed into a
cyclone where the powder is separated and collected. The spray
dryer can be assembled in a co-current configuration with a rotary
atomization nozzle and the nanosuspension can be fed to the rotary
atomizer using a peristaltic pump.
[0089] 2. Tableting
[0090] The controlled release nanoparticulate formulations of the
invention can be in the form of tablets for oral administration.
Preparation of such tablets can be by pharmaceutical compression or
molding techniques known in the art. The tablets of the invention
may take any appropriate shape, such as discoid, round, oval,
oblong, cylindrical, triangular, hexagonal, and the like.
[0091] The tablets may be coated or uncoated. If coated they may be
sugar-coated (to cover objectionable tastes or odors and to protect
against oxidation), film coated (a thin film of water soluble
matter for similar purposes), or enteric coated (to resist
dissolution in gastric fluid but allow disintegration of the
coating in the small intestine).
[0092] Tableting techniques known to one of ordinary skill in the
art are described in, for example, the 18th edition of Remington's
Pharmaceutical Sciences, Chapter 89, pp. 1633-1658 (Mach Publishing
Company, 1990), which is specifically incorporated by reference. In
the simplest procedure, the ingredients (except for any lubricant)
are blended together to provide a mixture having the active
ingredient uniformly dispersed throughout. A lubricant can then be
added and blended, and the tablets are compressed using an
appropriate tableting machine.
[0093] Formulations suitable for tableting are prepared using, for
example, a V-blender (Blend Master Lab Blender, Patterson Kelley
Co.). In an exemplary method, the nanoparticulate composition and
the one or more rate-controlling polymers are added to the
V-blender and blended periodically, followed by the addition of
other excipients, such as lactose, magnesium stearate, or PVP,
followed by periodic blending in the V-Blender.
[0094] Tableting can be accomplished by using, for example, a
Carver Press (Carver Laboratory Equipment). In such a method, the
correct amount of material is loaded into the punches, followed by
pressing together at the appropriate pressure and time interval,
and removal of the formed tablet.
[0095] Yet another exemplary method for creating tablets is
wet-granulation. Wet-granulation comprises mixing water and/or
granulating fluid to the dry materials (nanoparticulate composition
(comprising a drug and surface stabilizer), rate-controlling
polymer, and any additives). After thorough granulation, the
material is sieved through a coarse mesh screen and dried. The
material is then re-sieved through a fine mesh screen and blended
with, for example, magnesium stearate, followed by tableting to
create tablets.
[0096] Tablets are tested to determine that they meet the correct
hardness specifications. An exemplary tablet hardness tester is an
Erweka TBH 30 (Erweka Instruments, Inc.).
C. Administration of Controlled Release Nanoparticulate
Compositions or Dosage Forms
[0097] Yet another aspect of the present invention provides a
method of treating a mammal, including a human, requiring extended
administration of a drug or other agent. The administered
controlled release nanoparticulate composition releases an
incorporated drug or other agent over a prolonged period of time
providing a desired effect for a period from about 2 to about 24
hours or more.
[0098] In general, the compositions of the invention will be
administered to a mammalian subject in need thereof using a level
of drug or agent that is sufficient to provide the desired
physiological effect via any conventional method, such as orally,
rectally, buccally, or via the vagina. The mammalian subject may be
a domestic animal or pet but preferably is a human subject. The
level of drug or agent needed to give the desired physiological
result is readily determined by one of ordinary skill in the art by
referring to standard texts, such as Goodman and Gillman and the
Physician's Desk Reference.
[0099] The following examples are given to illustrate the present
invention. It should be understood, however, that the invention is
not to be limited to the specific conditions or details described
in these examples. Throughout the specification, any and all
references to a publicly available documents are specifically
incorporated into this patent application by reference.
Example 1
[0100] The purpose of this experiment was to demonstrate a
reasonable amount of controlled release with a nanoparticulate drug
formulation.
[0101] 29% w/w spray-dried nanoparticulate naproxen intermediate
(SDI) (containing 93% w/w nanoparticulate naproxen and 7% w/w
polyvinylpyrrolidone (PVP) as a surface stabilizer (sieve #20)),
30% w/w Klucel.RTM. HPC polymer (sieve #40), 40% w/w lactose
(Foremost #316 Fast-fib, sieve #40), and 1% w/w magnesium stearate
(Spectrum, sieve #40) were combined as follows to form a controlled
release nanoparticulate formulation tablet to be tested.
[0102] The average effective particle size of the nanoparticulate
naproxen prior to spray-drying to form spray-dried nanoparticulate
naproxen intermediate was 226 nm, with 90% of the particles having
a size of less than 297 nm. The spray-dried powder had a mean
particle size of about 26 .mu.m. This particle size information for
the naproxen SDI is applicable to the following Examples 2-10.
[0103] (The sources given in this example for the naproxen SDI,
PVP, Klucel.RTM. (an HPC polymer), lactose, and magnesium stearate
are also applicable to the following examples.)
[0104] The naproxen SDI and Klucel.RTM. were added to a V-blender
(Blend Master Lab Blender, Patterson Kelley Co.) and blended for 10
min. The lactose was then added to the blender and blended for 10
min. Finally, the magnesium stearate was added to the blender and
blended for 3 min.
[0105] This material was formed into tablets using a Carver Press
(Carver Laboratory equipment, model #3912). The resultant tablets
had a weight of 500 mg and a hardness of about 9 to about 12 kP
[0106] Testing for Controlled Release
[0107] A Distek Dissolution System (used with the Hewlett Packard
Diode Array Spectrophotometer 8452A and the Hewlett Packard Flow
Control device model 89092A) was used in testing for controlled
release. The temperature (37.degree. C.) and agitation of this
instrument simulates the body system as it attempts to dissolve the
drug in the tablet.
[0108] A phosphate buffer at pH 7.4 is used for the testing medium,
prepared as follows: 230.0 grams of sodium phosphate dibasic,
anhydrous (J.T. Baker) plus 52.4 grams of sodium phosphate
monobasic, dihydrate (J.T. Baker) added to 20.0 liters of deionized
water and stirred at 2300 rpm for two hours.
[0109] Phosphate buffer (900 ml) and a tablet were placed into a
container of the Distek System at 37.degree. C. The tablets were
agitated, resulting in dissolution of the tablets within a range of
40-50 min. Such a time period is not suitable for controlled
release applications.
Example 2
[0110] The purpose of this experiment was to demonstrate controlled
release with a nanoparticulate drug formulation.
[0111] To improve the controlled release characteristics of the
formed tablets, (i) the weight of the tablet was increased from 500
to 750 mg, (ii) the hardness of the tablet was increased from 9-12
to 35-37 kP; and (iii) 3% extra PVP was added as a binder agent in
place of 3% lactose.
[0112] Naproxen SDI (containing 93% w/w nanoparticulate naproxen
and 7% w/w PVP), 30% w/w Klucel.RTM. and 3% w/w PVP (Plasdone K-90
(Povidone USP), ISP Technologies) were combined as in Example 1 to
form a tablet of 750 mg with a hardness of 35-37 kP (the PVP was
added after addition of the lactose and blended for 5 additional
min. in the V-Blender prior to tableting). Quantities of each
component in the tablet are given below (mg).
TABLE-US-00001 Naproxen SDI Klucel .RTM. Lactose PVP Mg Stearate
217.5 225 277.5 22.5 7.5
[0113] Following testing with the Distek Dissolution System, the
results demonstrated a steady controlled release of drug over a
three hour time period, as shown in FIG. 1.
Example 3
[0114] The purpose of this experiment was to determine the effects
of the hardness of a tablet on controlled release of the
nanoparticulate agent.
[0115] Three separate hardnesses were tested simultaneously: 15 kP,
25 kP, and 35 kP. Tablets were made as in Example 1, comprising 29%
naproxen SDI, 30% Klucel.RTM., and 3% PVP. Quantities of each
component in each of the tablet formulations are given below
(mg).
TABLE-US-00002 Mg Hardness Naproxen SDI Klucel .RTM. Lactose PVP
Stearate 15 217.5 225 277.5 22.5 7.5 25 217.5 225 277.5 22.5 7.5 35
217.5 225 277.5 22.5 7.5
[0116] The results shown in FIG. 2 demonstrate that as the hardness
of a tablet increases, the controlled release characteristics of
the tablet also steadily increase. Tablets having a hardness of
about 15 kP, 25 kP, and 35 kP released naproxen for about 65 min.,
140 min., and 240 min., respectively, showing a direct correlation
between tablet hardness and increased controlled release of the
administered agent.
Example 4
[0117] The purpose of this experiment was to compare the controlled
release characteristics of two different rate-controlling polymers:
Klucel.RTM. HPC and Shinetzu.RTM. L-HPC.
[0118] Tablets were made as in Example 1, with 20% Klucel.RTM. HPC
(without the 3% PVP K-90) and with 20% Shinetzu.RTM. L-HPC.
Quantities of each component in each of the tablet formulations are
given below (mg).
TABLE-US-00003 Shinetzu .RTM. Mg Naproxen SDI Klucel .RTM. HPC
L-HPC Lactose Stearate 292.5 150 0 300 7.5 292.5 0 150 300 7.5
[0119] The resultant tablets had a hardness of 35 kP. The results,
shown in FIG. 3, demonstrate that the tablet with 20% Klucel.RTM.
as the polymer completely released within three to four hours, and
the tablet with 20% Shinetzu.RTM. L-HPC as the polymer allowed the
tablet to dissolve in only one hour.
Example 5
[0120] The purpose of this experiment was to compare the controlled
release characteristics of different grades of Methocel.RTM.
hydroxypropyl methyl cellulose (HPMC) used as the rate-controlling
polymer: (i) Methocel.RTM. K4M, (ii) Methocel.RTM. E4M, (iii)
Methocel.RTM. K15M, (iv) Methocel.RTM. K100LV, (v) Methocel.RTM.
K100LV, and (vi) Methocel.RTM. E10M.
[0121] Tablets were prepared as in Example 1, using a 20%
concentration of Methocel.RTM. HPMC. Quantities of each component
in each of the tablet formulations are given below (mg).
TABLE-US-00004 Naproxen SDI Methocel .RTM. HPMC Lactose Mg Stearate
292.5 150 (K4M) 300 7.5 292.5 150 (E4M) 300 7.5 292.5 150 (K15M)
300 7.5 292.5 150 (K100LV) 300 7.5 292.5 150 (K100LV) 300 7.5 292.5
150 HPMC E10M 300 7.5
[0122] The tablets had a hardness of about 35 to about 37 kP. Each
of the Methocel.RTM. grades tested in the Distek Dissolution
system, was found to exert some extent of controlled release on the
nanoparticulate formulation, as shown in FIG. 4. Methocel.RTM.
grades K4M, K15M, and K100M gave an extreme amount of controlled
release (40-50% in 12 hours), Methocel.RTM. grade E4M dissolved in
only about three hours, and Methocel.RTM. grades K100LV and E10M
gave a release over about 12 to about 14 hours.
Example 6
[0123] The purpose of this example was to determine the effect of
adding hydrogenated vegetable oil (Lubritab.RTM.) to controlled
release of a nanoparticulate agent.
[0124] Tablets were prepared as in Example 1, with 30% Klucel.RTM.
used as the rate-controlling polymer. 3% Lubritab.RTM. (Mendel, a
Penwest Company) was used in the tablets. The tablets had a
hardness of 20-22 kP. Quantities of each component in each of the
tablet formulations are given below (mg).
TABLE-US-00005 Naproxen SDI Klucel .RTM. Lactose Lubritab .RTM. Mg.
Stearate 217.5 225 300 0 7.5 217.5 225 262.5 37.5 7.5 217.5 225 225
75 7.5 217.5 225 150 150 7.5
[0125] As shown in FIG. 5, the addition of Lubritab.RTM. to a
nanoparticulate formulation can allow for an increase in controlled
release of the administered agent. While the composition containing
0% Lubritab.RTM. was completely released at about 60 min., the
composition containing 20% Lubritab.RTM. was released over about
175 min.
Example 7
[0126] The purpose of this example was to compare the controlled
release properties of a composition of a spray-dried
nanoparticulate formulation mixed with a rate-controlling polymer
and a powder composition of unmilled naproxen and surface
stabilizer blended with a rate-controlling polymer.
[0127] Tablets were prepared as in Example 1. The concentration of
the administered agent (naproxen) and surface stabilizer, PVP, was
the same for both compositions: 93% naproxen and 7% PVP. The
rate-controlling polymer used was Methocel.RTM. K100LV in a
concentration of 20%. Quantities of each component in each of the
tablet formulations are given below (mg).
TABLE-US-00006 Naproxen Mg SDI Naproxen + PVP Methocel .RTM. K100LV
Lactose Stearate 292.5 0 150 300 7.5 0 292.5 150 300 7.5
[0128] The tablets had a hardness of 30 kP. As shown in FIG. 6, the
composition of raw drug and surface stabilizer blended with a
rate-controlling polymer had a more prolonged release as compared
to the composition of the spray-dried nanoparticulate formulation
mixed with a rate-controlling polymer. The results indicate that
complete release of the composition of raw drug and stabilizer
blended with a rate-controlling polymer occurred after about 10
hours, while complete release of the spray-dried nanoparticulate
formulation mixed with a rate-controlling polymer was expected to
occur after about 13 to about 14 hours (complete release of the
latter composition had not occurred after 12 hours, when the
results were analyzed).
Example 8
[0129] The purpose of this example was to determine the effect of
rate-controlling polymer concentration on the controlled release
characteristics of nanoparticulate formulations.
[0130] The first test determined the controlled release
characteristics of a nanoparticulate formulation comprising 5%
Methocel.RTM. K100LV, and the second test determined the controlled
release characteristics of a nanoparticulate formulation comprising
10% Methocel.RTM. K100LV. Controlled release characteristics of a
nanoparticulate formulation comprising 20% Methocel.RTM. K100LV
were obtained in Example 9 (FIG. 6) and are repeated here.
[0131] Tablets were prepared as in Example 1, with quantities of
each component in each of the tablet formulations are given below
(mg).
TABLE-US-00007 Naproxen SDI Methocel .RTM. K100LV Lactose Mg
Stearate 405 37.5 300 7.5 367.5 75 300 7.5 292.5 150 300 7.5
[0132] The results, shown in FIG. 7, show that with tablets having
an identical hardness and varying rate-controlling polymer
concentrations, the tablet having the greatest rate-controlling
polymer concentration will have the most prolonged drug release
characteristics. The tablet having a 5% polymer concentration
completely released after about 50 min.; the tablet having a 10%
polymer concentration completely released after about 350 min.; and
the tablet having a 20% polymer concentration completely released
after about 650 min. Thus, increased polymer concentration in the
nanoparticulate formulation is directly correlated with prolonged
release of the administered agent.
Example 9
[0133] The purpose of this example was to determine the effect of
wet granulation on controlled release of nanoparticulate
formulations.
[0134] Tablets were formed as in Example 1, except that a small
amount of water was added into each mixture to form granules. The
granules were then sieved through a coarse mesh screen and dried.
The material was then re-sieved through a fine mesh screen, and
blended with magnesium stearate and lactose, followed by tableting
to create tablets. Quantities of each component in each of the
tablet formulations are given below (mg).
TABLE-US-00008 Naproxen Mg SDI KIucel .RTM. HPC Methocel .RTM. HPMC
Lactose Stearate 292.5 150 0 300 7.5 292.5 0 150 300 7.5
[0135] The results, shown in FIG. 8, indicate that for both
rate-controlling polymers, Klucel.RTM. HPC and Methocel.RTM. HPMC,
the tablets formed from wet granulation showed a much more
controlled release than the normal dry mixture. The prolonged
controlled release is likely due to the strong binding of the
granules formed by the wet granulation technique. This binding is
stronger than the binding of the materials by direct compression.
Thus, wet granulation improves controlled release.
Example 10
[0136] The purpose of this example was to prepare a controlled
release formulation of glipizide. Glipizide, also known as
1-cyclohexyl-3[[p-[21(5-methylpyrazine-carboxyamido)ethyl]-phenyl]-sulfon-
yl]-urea, is an oral sulfonylurea.
[0137] Glipizide and HPC-SL in the ratio of 10:3, were milled in a
Dyno-mill to produce a nanoparticulate glipizide dispersion. The
composition was milled for 6 hours, and the average effective
particle size of the glipizde was about 177 nm, with about 50% of
the particles having a size less than about 157 nm, and about 90%
of the particles having a size less than about 276 nm.
[0138] The nanoparticulate glipizide suspension was spray dried
using a Yamato GB-22.RTM. spray-dryer under following conditions to
produce a spray-dried glipizide intermediate (SDI): [0139] Inlet
temp.: 115.degree. C. [0140] Outlet temp.: 50.degree. C. [0141]
drying air 0.36 m.sup.3/min [0142] atomizing air 2.5
Kgf/cm.sup.2
[0143] The powder blend for the tablets comprised: 13 mg SDI, 241.6
mg Methocel.RTM. (K100LV), 483.3 mg lactose (Foremost #316), and
12.1 mg magnesium stearate, for a total of 750.0 mg. Each 750.0 mg
tablet contained 10 mg of the drug (glipizide)
[0144] The excipients were sieved, blended, and compressed using a
Carver press at 5,000 lb for 10 sec. The tablets were analyzed (at
274 nm) using the dissolution system as described above.
[0145] The results, shown in FIG. 9, indicate a steady release of
drug over a time period of just under 16 hours (i.e., about 950
minutes).
[0146] In Examples 11-15, all percentages are by weight unless
otherwise stated. The term "purified water" refers to water which
has been passed through a water filtration system.
Example 11
[0147] The purpose of this example was to prepare an uncoated
controlled release tablet formulation containing nanoparticulate
nifedipine.
[0148] A colloidal dispersion of nifedipine in water was prepared.
The dispersion contained 10% (w/w) of the drug and 2% hydroxypropyl
cellulose. Particle size analysis, performed using a Malvern
Mastersizer S2.14 (Malvern Instruments Ltd., Malvern,
Worcestershire, UK) recorded by a wet method using a 150 ml flow
through cell, revealed the following particle size characteristics:
D.sub.v,90 620 nm; D.sub.v,50 313 nm; D.sub.v,10 170 nm, with
97.47% of the colloidal particles being less than 1.03 .mu.m in
diameter. (Where D.sub.v,90 620 nm indicates that 90% of particles
had a size less than 620 nm, etc.).
[0149] The nifedipine dispersion was prepared for spray drying by a
series of four homogenization steps. The dispersion was homogenized
at medium shear for 5 min. Sodium lauryl sulphate (0.05%) was added
prior to homogenization at medium shear for a further 5 min. The
dispersion was then diluted 50:50 with purified water and
homogenized at medium shear for a further 10 min. Finally, mannitol
(10%) was added and the mixture was homogenized at high shear for
15 min. The final content of the mixture to be spray dried is given
in Table 1.
TABLE-US-00009 TABLE 1 Composition prior to spray drying for
Example 11 Ingredient Amount (% by wt.) Nifedipine dispersion 45.44
Purified water 45.44 Mannitol 9.09 Sodium lauryl sulphate 0.02
[0150] The mixture thus obtained was spray dried using a Buchi Mini
B-191 Spray Drier system (Buchi, Switzerland). The spray drying
conditions are summarized in Table 2. The spray dried nifedipine
particles thus prepared were then blended. The blend formulation is
given in Table 3.
TABLE-US-00010 TABLE 2 Spray drying conditions for Example 11
Parameter Level Inlet temperature 135.degree. C. Atomising pressure
setting 800 l/min Vacuum pressure 30-45 mbar Aspirator setting 100%
Spray rate 6 ml/min
[0151] The blend obtained after the previous step was tableted
manually using a Fette E1 tablet press (Wilheim Fette GmbH,
Schwarzembek, Germany) fitted with 11 mm round normal concave
tooling. The tablets produced had a mean tablet hardness of 122.7 N
and a mean tablet potency of 29.7 mg/tablet. In vitro dissolution
was carried out in phosphate-citrate buffer, pH 6.8, containing
0.5% sodium lauryl sulphate, using USP apparatus II (100 rpm).
Dissolution data is given in Table 4.
TABLE-US-00011 TABLE 3 Blend formulation for Example 11 Ingredient
Amount Spray dried nifedipine 17.92 Avicel PH102 30.01 Pharmatose
DCL 30.01 Methocel K 15M 20.00 Colloidal silicon dioxide 1.20
Magnesium stearate 0.86
TABLE-US-00012 TABLE 4 Dissolution data for uncoated nifedipine
tablets prepared according to Example 11 Time (hr) % Active
Released 1.0 17.8 2.0 24.9 4.0 37.1 6.0 49.1 8.0 61.5 10.0 71.5
22.0 108.8
Example 12
[0152] The purpose of this example was to prepare a coated
controlled release tablet formulation containing nanoparticulate
nifedipine.
[0153] Tablets prepared according to Example 11 were coated with a
Eudragit.RTM. L coating solution detailed in Table 5. Coating was
performed using an Manesty Accelacota 10'' apparatus (Manesty
Machine Ltd., Liverpool, UK) and a coating level of 5.5% solids
weight gain was achieved. Coating conditions are given in Table
6.
TABLE-US-00013 TABLE 5 Coating solution formulation Ingredient
Amount (%) Eudargit .RTM. L 12.5 49.80 Talc 2.49 Dibutyl sebecate
1.25 Isopropyl alcohol 43.46 Purified water 3.00
TABLE-US-00014 TABLE 6 Coating conditions Parameter Level Inlet
temperature 35-45.degree. C. Outlet temperature 32-36.degree. C.
Air pressure 1.4 bar Spray rate 27 g/min
[0154] In vitro dissolution was carried out according to the same
methodology used in Example 1: phosphate-citrate buffer, pH 6.8,
containing 0.5% sodium lauryl sulphate, using USP apparatus II (100
rpm). Dissolution data is given in Table 7.
TABLE-US-00015 TABLE 7 Dissolution data for coated nifedipine
tablets prepared according to Example 12 Time (hr) % Active
Released 1.0 4.3 2.0 11.5 4.0 24.0 6.0 38.0 8.0 58.3 10.0 66.4 22.0
99.6
[0155] FIG. 10 shows the mean in vivo plasma profiles in nine
fasted human volunteers for (1) nifedipine containing controlled
release matrix tablets coated with a controlled release coating
according to the present invention as described in Example 12; and
(2) a control composition. The study had a fully randomized, fully
crossed over, single dose administration design. From the figure it
can be seen that a controlled release composition prepared
according to Example 12 shows a high level of availability and
shows good controlled release characteristics over a 24 hour
period.
Example 13
[0156] The purpose of this example was to prepare an uncoated
controlled release tablet formulation containing nanoparticulate
glipizide.
[0157] A colloidal dispersion of glipizide in water was prepared.
The dispersion contained 10% (w/w) of the drug and 3% hydroxypropyl
cellulose. Particle size analysis, performed using a Malvern
Mastersizer S2.14, recorded by a wet method using a 150 ml flow
through cell, revealed the following particle size characteristics:
D.sub.v,90 650 nm; D.sub.v,50 386 nm; D.sub.v,10 290 nm.
[0158] The glipizide dispersion was prepared for spray drying by
adding 15% mannitol to the aqueous glipizide dispersion with
stirring. The final content of the mixture to be spray dried is
given in Table 8.
TABLE-US-00016 TABLE 8 Composition prior to spray drying for
Example 13 Ingredient Amount (% by wt.) Glipizide dispersion 10
Hydroxypropyl cellulose 3 Mannitol 15 Purified water 72
[0159] The mixture thus obtained was spray dried using a Buchi Mini
B-191 Spray Drier system. The spray drying condition are summarized
in Table 9.
TABLE-US-00017 TABLE 9 Spray drying conditions for Example 13
Parameter Level Inlet temperature 115-116.degree. C. Atomising
pressure setting 800 mbar Vacuum pressure 25-45 mbar Aspirator
setting 100% Spray rate 10 ml/min
[0160] The spray dried glipizide particles thus prepared were then
blended. The blend formulation is given in Table 10.
TABLE-US-00018 TABLE 10 Blend formulation for Example 13 Ingredient
Amount (% by wt.) Spray dried glipizide 3.36 Avicel .TM. pH101 35.8
Methocel K .TM. 100LV 60.0 Aerosil .TM. 200 0.4 Magnesium stearate
0.5
[0161] The blend obtained after the previous step was tableted
using a single station tablet press fitted with 9.5 mm round normal
concave tooling. The tablets produced had a mean tablet hardness of
149 N and a mean tablet potency of 9.1 mg/tablet. In vitro
dissolution was carried out in KH.sub.2PO.sub.4 buffer, pH 7.5,
using USP apparatus I (100 rpm). Dissolution data is given in Table
11.
TABLE-US-00019 TABLE 11 Dissolution data for uncoated glipizide
tablets prepared according to Example 13 Time (hr) % Active
Released 1.0 8.0 2.0 17.0 4.0 35.1 6.0 51.4 8.0 65.2 10.0 79.5 22.0
95.6
Example 14
[0162] The purpose of this example was to prepare delayed release
nanoparticulate nifedipine capsules.
[0163] A colloidal dispersion of nifedipine in water was prepared.
The dispersion contained 10% w/w Nifedipine, 2%
hydroxypropylcellulose, and 0.1% Sodium Lauryl Sulphate in water.
Particle size analysis, performed using a Malvern Mastersizer
S2.14, recorded by a wet method using a 150 ml flow through cell,
revealed the following particle size characteristics: Dv,90=490 nm;
Dv,50=290 nm; Dv,10=170 nm
[0164] The nifedipine dispersion was prepared for spray drying by
adding Purified Water and homogenizing for 5 minutes. Mannitol was
added and the resulting mixture was homogenized for 15 minutes. The
final content of the mixture to be spray dried is given in Table
12.
TABLE-US-00020 TABLE 12 Composition prior to spray drying for
Example 14 Ingredient Amount (% by wt.) Nifedipine dispersion 45.45
Mannitol 9.09 Purified water 45.45
[0165] The mixture thus obtained was spray dried using a Buchi Mini
B-191 Spray Drier system. The spray drying conditions are
summarized in Table 13.
TABLE-US-00021 TABLE 13 Spray drying conditions for Example 14
Parameter Level Inlet temperature 135.degree. C. Atomising pressure
setting 800 mbar Aspirator setting 100% Flow rate 6 ml/min
[0166] The spray dried nifedipine particles thus prepared were then
blended. The blend formulation is given in Table 14.
TABLE-US-00022 TABLE 14 Blend formulation for Example 14 Ingredient
Amount (% by wt.) Spray dried nifedipine 10.40 (Dv, 90 ca 500 nm)
Avicel .TM. pH102 77.05 Explotab 10.00 Colloidal Silicon Dioxide
1.00 Magnesium stearate 1.50
[0167] The resulting blend was tableted using a Fette P2100 rotary
tablet press (Wilhelm Fette GmbH, Schwarzenbek, Germany) fitted
with 3.8 mm shallow concave multi-tipped tooling. The tablets had a
mean set up hardness of 56 N and a mean set up weight of 34.46
mg.
[0168] The tablets thus obtained were coated in a Hi-Coater (Vector
Corp., Marion, Iowa, USA) with the Eudragit S coating solution
detailed in Table 15. A coating level of 10.03% solids weight gain
was achieved.
TABLE-US-00023 TABLE 15 Coating Solution Formulation for Example 14
Ingredient Amount (% by wt.) Eudragit S 12.5 50.0 Talc 2.50 Dibutyl
Sebecate 1.25 Isopropyl Alcohol 43.25 Purified Water 3.00
[0169] The coated minitablets thus obtained were hand-filled into
hard gelatin capsules to form Nifedipine 10 mg Capsules (9
minitablets/capsule). In vitro dissolution was carried out in
citrate-phosphate buffer, pH 6.8, containing 0.5% Sodium Lauryl
Sulphate, using a USP apparatus II (100 rpm). The dissolution data
of the resulting capsules is given in Table 16.
TABLE-US-00024 TABLE 16 Dissolution data for Nifedipine 10 mg
capsules prepared according to Example 14 Time (hr) % Active
Released 0.25 3.99 0.5 4.60 0.75 21.10 1.0 93.07 1.5 100.39 2.0
100.79
Example 15
[0170] The purpose of this example was to prepare a control for
delayed release nanoparticulate nifedipine capsules. The control
does not contain a nanoparticulate composition.
[0171] Nifedipine raw material (Dv,90=673 .mu.m), Explotab, and
Avicel pH 102 were mixed in the Gral 25 (NV-Machines Colett SA,
Wommelgam, Belgium) for 10 minutes at 1000 rpm. Purified water was
gradually added with mixing until granulation was achieved. The
granulate was oven dried for 18 hours at 50.degree. C. The dried
granulate was milled through a 50 mesh screen using a Fitzmill M5A
(The Fitzpatrick Co. Europe, Sint-Niklaas, Belgium). The final
content of the granulate is summarized in Table 17.
TABLE-US-00025 TABLE 17 Final composition of Granulate for Example
15 Ingredient Amount (% by wt.) Nifedipine 7.68 Explotab 24.22
Avicel pH 102 68.10
[0172] The granulate thus obtained (Dv,90=186 .mu.m) was then
blended. The blend formulation is given in Table 18.
TABLE-US-00026 TABLE 18 Blend Formulation for Example 15 Ingredient
Amount (% by wt.) Nifedipine Granulate 41.28 (Dv, 90 = 186 .mu.m)
Avicel pH102 56.22 Colloidal Silicon Dioxide 1.00 Magnesium
Stearate 1.50
[0173] The particle size analysis of the starting nifedipine raw
material and the milled nifedipine granulate, performed using the
Malvern Mastersizer S with a 1000 mm lens (nifedipine raw material)
and a 300 mm lens (milled nifedipine granulate) recorded by a dry
powder method, revealed the particle size characteristics given in
Table 19.
TABLE-US-00027 TABLE 19 Particle Size Analysis of Nifedipine
Compositions Size Range Raw Nifedipine Milled Nifedipine Granulate
Dv, 90 673 .mu.m 186 .mu.m Dv, 50 234 .mu.m 103 .mu.m Dv, 10 14
.mu.m 32 .mu.m
[0174] The resulting blend was tableted using a Fette P2100 rotary
tablet press fitted with 3.8 mm shallow concave multi-tipped
tooling. The tablets had a mean set up hardness of 47 N and a mean
set up weight of 35 mg. The tablets thus obtained were coated in a
Hi-Coater with the Eudragit S coating solution detailed in Table
20. A coating level of 10.34% solids weight gain was achieved.
TABLE-US-00028 TABLE 20 Coating Solution Formulation for Example 15
Ingredient Amount (% by wt.) Eudragit S 12.5 50.0 Talc 2.50 Dibutyl
Sebecate 1.25 Isopropyl Alcohol 43.25 Purified Water 3.00
[0175] The coated minitablets thus obtained were hand-filled into
hard gelatin capsules to form nifedipine 10 mg capsules (9
minitablets/capsule). In vitro dissolution was carried out in
citrate-phosphate buffer, pH 6.8, containing 0.5% Sodium Lauryl
Sulphate, using USP apparatus II (100 rpm). The dissolution data
for the resulting capsules is given in Table 21.
TABLE-US-00029 TABLE 21 Dissolution data for Nifedipine 10 mg
capsules prepared according to Example 15 Time (hr) % Active
Released 0.25 8.83 0.5 32.50 0.75 77.88 1.0 85.26 1.5 91.30 2.0
94.46
Example 16
[0176] FIG. 11 shows the mean in-vivo plasma profiles of nifedipine
in ten fasted human volunteers for (1) a controlled release
composition manufactured according to the present invention as
described in Example 14 (nifedipine 10 mg capsules (Dv,90 ca 500
nm)); and (2) a control composition manufactured as described in
Example 15 (nifedipine 10 mg capsules (Dv,90=186 .mu.m)). The study
had a single dose, fully randomized, fully crossed over, oral
administration design. From the Figure it can be seen that the
controlled release composition manufactured according to the
present invention shows an initial lag time followed by a rapid and
high level of availability of active.
[0177] It should be noted that the controlled release composition
manufactured in accordance with the invention showed a relative
bioavailability of 1.45 (i.e., 45% enhanced bioavailability as
compared with the control).
[0178] It will be apparent to those skilled in the art that various
modifications and variations can be made in the methods and
compositions of the present invention without departing from the
spirit or scope of the invention. Thus, it is intended that the
present invention cover the modifications and variations of this
invention provided they come within the scope of the appended
claims and their equivalents.
* * * * *