U.S. patent application number 16/196253 was filed with the patent office on 2019-03-21 for orally disintegrating tablet formulation for enhanced bioavailability.
This patent application is currently assigned to Kashiv Pharma, LLC. The applicant listed for this patent is Kashiv Pharma, LLC. Invention is credited to Murali Mohan Bommana, Jelena Djordjevic, Wantanee Phuapradit, Christopher A. Pizzo, Navnit H. Shah.
Application Number | 20190083403 16/196253 |
Document ID | / |
Family ID | 49950054 |
Filed Date | 2019-03-21 |
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United States Patent
Application |
20190083403 |
Kind Code |
A1 |
Djordjevic; Jelena ; et
al. |
March 21, 2019 |
Orally Disintegrating Tablet Formulation For Enhanced
Bioavailability
Abstract
In some aspects of the present invention is a formulation
comprising a solid dispersion or intimate mixture of a poorly water
soluble drug and an ionic polymer surprisingly exhibiting fast
disintegration of tablet.
Inventors: |
Djordjevic; Jelena; (Basking
Ridge, NJ) ; Bommana; Murali Mohan; (Plainsboro,
NJ) ; Phuapradit; Wantanee; (Montville, NJ) ;
Shah; Navnit H.; (Clifton, NJ) ; Pizzo; Christopher
A.; (Ridgewood, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Kashiv Pharma, LLC |
Bridgewater |
NJ |
US |
|
|
Assignee: |
Kashiv Pharma, LLC
Bridgewater
NJ
|
Family ID: |
49950054 |
Appl. No.: |
16/196253 |
Filed: |
November 20, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14653071 |
Jun 17, 2015 |
10195150 |
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PCT/US2013/076578 |
Dec 19, 2013 |
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16196253 |
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61749040 |
Jan 4, 2013 |
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61739813 |
Dec 20, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0056 20130101;
A61K 31/57 20130101; A61K 31/4985 20130101; A61K 31/4045 20130101;
A61K 31/496 20130101; A61K 9/2054 20130101; A61K 9/146 20130101;
A61K 9/2027 20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 9/00 20060101 A61K009/00; A61K 31/57 20060101
A61K031/57; A61K 31/4045 20060101 A61K031/4045; A61K 9/14 20060101
A61K009/14; A61K 31/4985 20060101 A61K031/4985; A61K 31/496
20060101 A61K031/496 |
Claims
1. An orally disintegrating tablet comprising: an amorphous solid
dispersion comprising a hot-melt extrudate comprising a poorly
water soluble drug and an ionic polymer, wherein the ionic polymer
is selected from the group consisting of: a copolymer of
methacrylic acid, ethyl acrylate, and methyl methacrylate;
hypromellose acetate succinate; and a copolymer of
dimethylaminoethyl methacrylate, butyl methacrylate, and methyl
methacrylate, wherein the ionic polymer is present in an amount of
at least 55% by weight of the amorphous solid dispersion, wherein
the poorly water soluble drug and the ionic polymer are present in
a weight ratio of between 20:80 and 45:55, wherein the poorly water
soluble drug in amorphous form is present in the amount of at least
80% by weight of the poorly soluble drug, and wherein the tablet
disintegrates in water within 40 seconds or less.
2. The orally disintegrating tablet of claim 1, wherein an amount
of the ionic polymer is at least about 65% by weight of said
dispersion.
3. The orally disintegrating tablet of claim 1, wherein the poorly
water soluble drug is megestrol or a pharmaceutically acceptable
salt thereof.
4. The orally disintegrating tablet of claim 1, wherein the poorly
water soluble drug is ziprasidone or a pharmaceutically acceptable
salt thereof.
5. The orally disintegrating tablet of claim 1, wherein the poorly
water soluble drug is eszopiclone or a pharmaceutically acceptable
salt thereof.
6. The orally disintegrating tablet of claim 1, wherein the poorly
water soluble drug is prednisolone or a pharmaceutically acceptable
salt thereof.
7. The orally disintegrating tablet of claim 1, wherein the poorly
water soluble drug is clarithromycin or a pharmaceutically
acceptable salt thereof.
6. The orally disintegrating tablet of claim 1, wherein the poorly
water soluble drug is sumatriptan or a pharmaceutically acceptable
salt thereof.
7. The orally disintegrating tablet of claim 1, wherein the drug
and the ionic polymer are present in a weight ratio of 20:80, and
wherein the tablet disintegrates in 40 seconds or less.
8. The orally disintegrating tablet of claim 1, wherein the drug
and the ionic polymer are present in a weight ratio of 45:55, and
wherein the tablet disintegrates in 30 seconds or less.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S. patent
application Ser. No. 14/653,071, filed Jun. 17, 2015, which is a
national phase entry under 35 U.S.C. .sctn. 371 of International
Application No. PCT/US2013/076578, filed Dec. 19, 2013, published
as WO 2014/100418 A2, which claims the benefit of the filing dates
of U.S. Provisional Application No. 61/739,813, filed on Dec. 20,
2012, and U.S. Provisional Application No. 61/749,040, filed on
Jan. 4, 2013, all of which are hereby incorporated herein by
reference.
BACKGROUND
[0002] This disclosure generally relates to formulations containing
active pharmaceutical ingredients that have low solubility in
water. In aspects, the formulations are solid oral dosage forms.
Embodiments of formulations include orally disintegrating
tablets.
[0003] Many therapeutically useful drug substances have low aqueous
solubility and/or low intestinal permeability. These properties
complicate the design of dosage forms for delivering the drug
substances. The Biopharmaceutics Classification System ("BCS") has
been developed to describe drug substances by their solubility and
permeability properties:
[0004] Class I--high permeability, high solubility drugs that are
well absorbed.
[0005] Class II--high permeability, low solubility drugs having
bioavailability that is limited by the solubilization rate.
[0006] Class III--low permeability, high solubility drugs having
bioavailability that is limited by the permeation rate.
[0007] Class IV--low permeability, low solubility drugs having poor
bioavailability and high variability of pharmacokinetics parameters
(e.g., AUC and C.sub.max).
[0008] A drug is considered to be highly soluble under the BCS when
its highest unit dosage strength is soluble in 250 mL or less of
aqueous media over the pH range of 1 to 7.5. Many drug substances,
however, fall within Classes II and IV. Formulating dosage forms to
deliver such drugs, particularly when larger amounts of the drugs
must be delivered in each dose, is very challenging. The absolute
drug solubility is not always the most important parameter, since
residence times in various sites within the gastrointestinal system
after oral administration vary, and it is usually necessary to have
a drug in solution during its transit through the particular sites
where it can be systemically absorbed. Examples of drugs having low
solubility are those that form solutions with water having
concentrations no greater than 1 mg/mL, or no greater than 0.1
mg/mL.
[0009] Various approaches for improving the solubility properties
of drugs have been used. For many substances, solubility can be
enhanced by reducing the particle sizes; an increased particle
surface area generally results in a more rapid dissolution rate.
Sometimes, different polymorphic forms, including crystalline,
solvated, and amorphous forms, will have different solubilities and
a suitable form can be chosen to meet a specific requirement.
However, these approaches are not without difficulties, since very
small particles generally have poor flow and handling properties
that can affect drug content uniformity, and many polymorphic forms
do not have sufficient physical stability to undergo formulation
processing and the subsequent storage over a typical product shelf
life, without converting to a different form.
[0010] The amorphous particles can have increased solubility by
overcoming crystal lattice energy. Typically, amorphous drug
particles are thermodynamically metastable compared to crystalline
states of the substance, but can have significantly enhanced
solubility and bioavailability. Solubility can be further
classified as equilibrium and supersaturation solubilities.
"Equilibrium solubility" is the solubility of the substance in a
specific fluid environment, in the absence of a solubilization aid.
"Supersaturation" refers to the solubility state of a substance in
excess of its equilibrium solubility, characterized by a solubility
that is greater than that defined by native solubility of the
substance in a given fluid environment. By converting a drug from a
crystalline to amorphous form, it is possible to achieve a
supersaturation solubility, which in turn can enhance
bioavailability. However, significant challenges of chemical and
physical drug instability remain. The amorphous state can be viewed
as a pseudo-solution state demonstrating greater chemical
reactivity, which is reflected in reduced physical and chemical
stability and shelf-life. Certain drugs have been commercialized in
the amorphous state, where the amorphous form of the drug substance
either has acceptable stability over the normal shelf-life of the
product, or can be stabilized by other formulation components. In
addition, some drugs have been successfully commercialized in a
thermodynamically metastable crystalline state.
[0011] Amorphous solid dispersion have been used to stabilize
amorphous material. A solid dispersion is formed from at least two
different components, generally (a) a polymer that can be either
crystalline or amorphous and (b) a hydrophobic drug that can be
dispersed molecularly, in amorphous particles (clusters) or in
crystalline particles. Polymers can improve the physical stability
of amorphous drugs in solid dispersions by increasing the glass
transition temperature (T.sub.g) of the miscible mixture, thus
reducing the molecular mobility at usual storage temperatures, or
by interacting specifically with functional groups of the drugs.
For a polymer to be effective in preventing crystallization, it has
to be molecularly miscible with the drug. However, to date,
limitations in the development of solid dispersions are
predominantly due to physical instability of these systems.
Polymeric materials are not in thermodynamic equilibrium below
their T.sub.g, so the solid polymer approaches its more stable
state (lower energy). Also, the effect of moisture on the storage
stability of amorphous material is very important as it may
increase drug mobility and promote drug crystallization. In
addition, many of the polymers used in solid dispersions can absorb
moisture, which may result in phase separation, crystal growth or
conversion from the amorphous to the crystalline state or from a
metastable crystalline form to a more stable structure during
storage, all of which may result in decreased solubility and
dissolution rate.
[0012] For certain patients, swallowing a typical solid
pharmaceutical dosage form is difficult. These patients can be
elderly, very young, suffering from psychiatric disorders, have
oral or esophageal dysfunctions or deformities, etc. When a solid
dosage form is preferable, such as to reduce the chances for dosing
errors, products have been developed that rapidly disintegrate
while being retained in the oral cavity. This disintegration can be
a decomposition of the tablet matrix into very small particles
and/or dissolution of the matrix in saliva, thereby facilitating
swallowing.
[0013] An orally disintegrating tablet ("ODT") has been defined by
the United States Food and Drug Administration as a solid dosage
form containing a medicinal substance that disintegrates rapidly,
usually within a matter of seconds, when placed upon the tongue. In
general, disintegration is expected to occur within about 30
seconds after the dosage form enters the oral cavity. Such dosage
forms are useful for treating pediatric and geriatric patients
having difficulties with swallowing tablets, capsules, etc., as
well as psychiatric patients having an aversion to the customary
swallowed solid forms. The action of saliva is sufficient to
achieve the desired result, and mechanical disintegration, such as
by chewing, is not required. Desirably, no external liquids will be
necessary for swallowing the disintegrated dosage form. An ODT is
also sometimes called an "orodispersible" tablet.
[0014] The ODT dosage form has certain important requirements, for
patient acceptability; these requirements are in addition to the
proper disintegration times. Frequently, the taste of the drug
substance will be masked, since many substances have bitter or
otherwise unpleasant tastes. Also, the mouth feel of the
disintegrated tablet is important, so grittiness and the sensation
of a residue in the mouth after swallowing should be avoided.
[0015] There are several techniques currently in use for making ODT
products, including freeze drying or lyophilization of solutions or
suspensions, compression of powder blends, molding of melts or
pastes, melt granulation, and others. Most of the techniques will
prepare tablets that are rather porous to aqueous fluids, thereby
promoting rapid disintegration of the matrix in saliva.
[0016] An early approach to preparing an orally disintegrating
tablet was described in U.S. Pat. No. 4,758,598, where a drug is
physically trapped in a freeze-dried matrix composed of a filler
(e.g., mannitol) and a polymer (e.g., gelatin). The product is a
rather fragile, low-density porous wafer, packaged in the plastic
tray where it was formed in a lyophilizer. More recently, U.S. Pat.
No. 5,763,476 described an asenapine maleate product prepared in
this manner; the drug will be released into saliva and, due to its
moderate aqueous solubility, undergoes systemic absorption through
the oral mucosa. Other current products are manufactured using this
technique.
[0017] Although the perception may be that rapid disintegration
leads to rapid rates of absorption and bioavailability, this is
frequently not observed with poorly soluble drugs. Following dosage
form disintegration, it still is necessary for the drug to dissolve
before it can be absorbed. It would be advantageous to
simultaneously provide rapid disintegration and a drug solubility
enhancement in a dosage form.
[0018] There is a continuing need for improved pharmaceutical
formulations containing low solubility drugs, providing features of
oral fast disintegration and higher drug solubility, and therefore
faster onset of action for poorly soluble drugs for certain
therapeutic classes to improve patient compliance.
SUMMARY OF THE INVENTION
[0019] In one aspect of the present invention is an orally
disintegrating tablet comprising a dispersion of a poorly water
soluble drug and an ionic polymer, wherein said ionic polymer is
present in an amount to maintain said poorly water soluble drug in
a substantially amorphous form, and wherein said ionic polymer is
selected such that said tablet disintegrates within about 30
seconds, and wherein said tablet further comprises at least one
additive, excipient, or carrier. In some embodiments, the drug is
megestrol or a pharmaceutically acceptable salt thereof.
[0020] In one aspect of the present invention is a formulation
comprising a solid dispersion or intimate mixture of a poorly water
soluble drug and an ionic polymer, wherein said ionic polymer is
present in an amount to maintain said poorly water soluble drug in
a substantially amorphous form, and wherein said ionic polymer is
present in an amount of at least 45% by weight of said formulation.
In some embodiments, the ionic polymer is present in an amount of
at least about 50% by weight of said formulation. In some
embodiments, the ionic polymer is present in an amount of at least
about 65% by weight of said formulation. In some embodiments, the
ionic polymer is present in an amount ranging from between about
55% to about 75% by weight of said formulation.
[0021] In some embodiments, the polymer is an anionic polymer. In
some embodiments, the anionic polymer is a copolymer of methacrylic
acid and an acrylate selected from the group consisting of ethyl
acrylate, methacrylate, and methyl methacrylate.
[0022] In some embodiments, the polymer is a cationic polymer. In
some embodiments, the cationic polymer is based on a copolymer of
dimethylaminoethyl methacrylate, butyl methacrylate, and methyl
methacrylate.
[0023] In some embodiments, the polymer is a mixture of acetic acid
and monosuccinic acid esters of hydroxypropyl methylcellulose.
[0024] In some embodiments, the poorly water soluble drug is
present in an amount ranging from about 5% to about 75% by weight
of said formulation. In some embodiments, the poorly water soluble
drug is present in an amount ranging from about 20% to about 50% by
weight of said formulation. In some embodiments, the poorly water
soluble drug is present in an amount ranging from about 30% to
about 50% by weight of said formulation. In some embodiments, the
poorly water soluble drug is selected from the group consisting of
analgesics, hypnotics, agents for treating bipolar disorder, agents
for treating schizophrenia, and agents for treating the central
nervous system. In some embodiments, the poorly water soluble drug
is selected from the group consisting of megestrol, ziprasidone,
eszopiclone, and sumatriptan or pharmaceutically acceptable acids,
salts or hydrates thereof.
[0025] In some embodiments, the ionic polymer is selected such that
said dispersion maintains a glass transition temperature between
about 50.degree. C. to about 150.degree. C. In some embodiments,
the ionic polymer is selected such that said dispersion maintains a
glass transition temperature between about 50.degree. C. to about
120.degree. C. In some embodiments, the composition further
comprises at least one additive, excipient or carrier. In some
embodiments, the at least one additive, excipient, or carrier is
selected from the group consisting of diluents, binders, drug
stabilizers, disintegrants, glidants, lubricants, release rate
modifiers, anti-oxidants, coatings, colorants, sweeteners, and
flavoring agents.
[0026] Another aspect of the present invention is an orally
disintegrating tablet formulation comprising a dispersion of a
poorly water soluble drug and an ionic polymer, wherein said ionic
polymer is present in an amount to maintain said poorly water
soluble drug in a substantially amorphous form, and wherein said
ionic polymer is present in an amount of at least 45% by weight of
said formulation and at least one pharmaceutically acceptable
additive, excipient, or carrier. In some embodiments, the average
particle size of said dispersion ranges from about 100 .mu.m to
about 350 .mu.m.
[0027] In some embodiments is a method of treating a subject
comprising administering a formulation comprising a dispersion of a
poorly water soluble drug and an ionic polymer, wherein said ionic
polymer is present in an amount to maintain said poorly water
soluble drug in a substantially amorphous form, and wherein said
ionic polymer is present in an amount of at least 45% by weight of
said formulation and at least one pharmaceutically acceptable
additive, excipient, or carrier.
[0028] In another aspect of the present invention is a formulation
comprising megestrol and an ionic polymer, wherein said ionic
polymer is present in an amount to maintain said poorly water
soluble drug in a substantially amorphous form, and wherein said
ionic polymer is present in an amount of at least 65% by weight of
said formulation.
[0029] In some embodiments of the present invention, the orally
disintegrating tablets surprisingly exhibited fast disintegration
and enhanced dissolution and bioavailability. In some embodiments,
an ionic polymer is selected so as to provide the aforementioned
fast disintegration and enhanced dissolution/bioavailability.
[0030] In another aspect is a pharmaceutical formulation containing
an intimate mixture comprising an amorphous drug having low aqueous
solubility and at least one poorly water-soluble ionic polymer. In
some embodiments, the intimate mixture is obtained from a molten
combination of the drug and polymer. In some embodiments, the
intimate mixture is obtained by precipitation from a solution
containing the drug and polymer. In some embodiments, the mixture
is in the form of an orally disintegrating tablet. In some
embodiments, the drug is megestrol or a salt thereof. In some
embodiments, the drug is megestrol acetate.
[0031] In another aspect, of the present invention is a composition
comprising a drug having low aqueous solubility.
[0032] In another aspect of the present invention is an orally
disintegrating tablet pharmaceutical formulation containing an
intimate mixture comprising an amorphous drug having low aqueous
solubility and at least one cationic polymer.
[0033] In another aspect is an orally disintegrating tablet
pharmaceutical formulation containing an intimate mixture
comprising an amorphous drug having low aqueous solubility and at
least one anionic polymer. In some embodiments, the intimate
mixture is obtained from a molten combination of the drug and
polymer. In some embodiments, the intimate mixture is obtained by
precipitation from a solution containing the drug and polymer. In
some embodiments, the polymer is an amino methacrylate copolymer.
In some embodiments, the polymer is a methacrylic acid copolymer,
Type A. In some embodiments, the polymer is a methacrylic acid
copolymer, Type B. In some embodiments, the polymer is a
methacrylic acid copolymer, Type C. In some embodiments, the
polymer is a hypromellose acetate succinate.
[0034] Without wishing to be bound by any particular theory, it has
now been discovered that amorphous solid dispersion of poorly
soluble drugs prepared with ionic polymers exhibits fast
disintegration property when compressed into tablets and therefore
is suitable for ODT dosage forms with faster onset of action.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] FIG. 1 illustrates comparative X-ray powder diffraction
("XRPD") patterns of initial and stored samples of composition 1A
from Example 1.
[0036] FIG. 2 illustrates comparative XRPD patterns of initial and
stored samples of composition 1D from Example 1
[0037] FIG. 3 illustrates comparative XRPD patterns of composition
2E from Example 2, having varying drug to polymer ratios.
[0038] FIG. 4 is a graphical representation of solubility data for
compositions from Example 3.
[0039] FIG. 5 is a graphical representation of solubility date for
ODT compositions.
DETAILED DESCRIPTION
[0040] In some aspects of the present invention is a formulation
comprising a dispersion or intimate mixture of a poorly water
soluble drug and an ionic polymer. In other aspects of the present
invention is a formulation comprising a dispersion or intimate
mixture of a poorly water soluble drug and an ionic polymer,
wherein said ionic polymer is present in an amount to maintain said
poorly water soluble drug in a substantially amorphous form. In yet
other aspects of the present invention is a formulation comprising
a dispersion or intimate mixture of a poorly water soluble drug and
an ionic polymer, wherein said ionic polymer is present in an
amount to maintain said poorly water soluble drug in a
substantially amorphous form and wherein said ionic polymer is
present in an amount of at least 50% by weight of said
formulation.
[0041] As used herein, the term "substantially" means to meet the
criteria in such measure that one skilled in the art would
understand that the benefit to be achieved, or the condition or
property value desired, is met. In some embodiments, the amount of
active agent present in amorphous form is generally in an amount of
at least 80% by total weight of the active agent present. In some
embodiments, the amount of active agent present in amorphous form
is generally in an amount of at least 85% by total weight of the
active agent present. In some embodiments, the amount of active
agent present in amorphous form is generally in an amount of at
least 90% by total weight of the active agent present. In some
embodiments, the amount of active agent present in amorphous form
is generally in an amount of at least 92.5% by total weight of the
active agent present. In some embodiments, the amount of active
agent present in amorphous form is generally in an amount of at
least 95% by total weight of the active agent present. In some
embodiments, the amount of active agent present in amorphous form
is generally in an amount of at least 97.5% by total weight of the
active agent present. In some embodiments, the amount of active
agent present in amorphous form is generally in an amount of at
least 99% by total weight of the active agent present.
[0042] Aspects of the present disclosure are directed to
pharmaceutical formulations of drugs having low solubility in
water. Pharmaceutical products can be tested for their drug
dissolution characteristics, such as using test 711 "Dissolution"
in United States Pharmacopeia 24, United States Pharmacopeial
Convention, Inc., Rockville, Md., 1999 (the "USP"). Various fluids
can be used as the dissolution media, including acids, buffers,
simulated digestive tract fluids, etc., and many of these are
defined in various monographs of the USP. An example of a procedure
uses "Apparatus 2," which has a vessel containing a medium that is
stirred with a rotating paddle. Typically, a dosage unit is
immersed into the medium and samples of the medium are withdrawn at
intervals for drug content analysis, frequently using high
performance liquid chromatography ("HPLC") techniques.
[0043] The disintegration times of pharmaceutical dosage forms can
be determined using the procedure of test 701 "Disintegration" in
the USP.
[0044] There are various methods currently used for determining the
intestinal permeability parameter of drugs, including both in vitro
and in vivo techniques. Some of these have been reviewed by D.
Volpe, "Application of Method Suitability for Drug Permeability
Classification," The AAPS Journal, Vol. 12(4), pages 670-678,
December 2010.
[0045] As used herein, the terms "drugs," "active agents," and
"active pharmaceutical ingredients" are used interchangeably.
[0046] Suitable drugs for preparing formulations include, but are
not limited to, members of the therapeutic categories analgesics,
anti-inflammatory agents, anthelmintics, anti-arrhythmic agents,
anti-bacterial agents, anti-viral agents, anticoagulants,
anti-depressants, anti-diabetic agents, anti-epileptic agents,
anti-fungal agents, anti-gout agents, anti-hypertensive agents,
anti-malarial agents, anti-migraine agents, anti-muscarinic agents,
anti-neoplastic agents, erectile dysfunction improving agents,
immunosuppressants, anti-protozoa agents, anti-thyroid agents,
anti-anxiolytic agents, sedatives, hypnotics, neuroleptics,
.beta.-blockers, cardiac inotropic agents, corticosteroids,
diuretics, anti-Parkinsonian agents, gastrointestinal agents,
histamine receptor antagonists, keratolytics, lipid regulating
agents, anti-angina agents, cox-2 inhibitors, leucotriene
inhibitors, macrolides, muscle relaxants, nutritional agents,
opioid analgesics, protease inhibitors, sex hormones, stimulants,
anti-osteoporosis agents, anti-obesity agents, cognition enhancers,
anti-urinary incontinence agents, nutritional oils, anti-benign
prostate hypertrophy agents, essential fatty acids, non-essential
fatty acids, and any combinations of two or more thereof.
[0047] Specific examples of suitable active pharmaceutical
ingredients include, but are not limited to: abiraterone,
acutretin, albendazole, albuterol, aminogluthemide, amiodarone,
amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone,
azithromycin, baclofen, beclomethsone, benezepril, benzonatate,
betamethasone, bicalutanide, boceprevir, budesonide, bupropion,
busulphan, butenafine, calcifediol, calciprotiene, calcitriol,
camptothecan, candesartan, capsaicin, carbamezepine, carotenes,
celecoxib, cerivistatin, cetrizine, chlorpheniramine,
cholecalciferol, cilostazol, cimetidine, cinnarizine,
ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene,
clomipramine, clopidrogel, codeine, coenzyme Q10, cyclobenzaprine,
cyclosporine, danazol, dantrolene, dexchlopheniramine, diclofenac,
dicoumarol, digoxin, dihydroepiandrosterone, dihydroergotamine,
dihydrotachysterol, dirithromycin, donepezil, efavirenz, eposartan,
ergocalciferol, ergotamine, essential fatty acid sources,
eszopiclone, etodolac, etoposide, famotidine, fenofibrate,
fentanyl, fexofenadine, finasteride, flucanazole, flurbiprofen,
fluvastatin, fosphenytion, frovatriptan, furazolidone, gabapentin,
gemfibrozil, glibenclamide, glipizide, glyburide, glymepride,
griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan,
isosorbide, isotreinoin, itraconazole, ivermectin, ketoconazole,
ketorolac, lamotrigine, lanosprazole, leflunomide, lisinopril,
loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene,
medroxyprogesterone, mefepristone, mefloquine, megesterol,
metaxalone, methadone, methoxsalen, metronidazole, metronidazole,
miconazole, midazolam, miglitol, minoxidil, mitoxantrone,
montelukast, nabumetone, nalbuphine, naratiptan, nelfinavir,
nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine,
omeprazole, oprevelkin, osteradiol, oxaprozin, paclitaxel,
paricalcitol, paroxetine, pentazocine, pioglitazone, pizofetin,
pravastatin, prednisolone, probucol, progesterone, pseudoephedrine,
pyridostigmine, rabeprazole, raloxifene, refocoxib, repaglinide,
rifabutine, rifapentine, rifaximine, rimexolone, ritanovir,
rizatriptan, rosiglitazone, saquinavir, sertraline, sibutramine,
sildenafil, simvastatin, sirolimus, spironolactone, sumatriptan,
tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene,
telaprevir, telmisartan, teniposide, terbinafine, terzosin,
tetrahydrocannabinol, tiagabine, ticlidopine, tirofibran,
tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin,
troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine,
vertoporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin
K, zafirlukast, zileuton, ziprasidone, zolmitriptan, zolpidem, and
zopiclone. This listing is not intended to be exhaustive, as many
other drug substances can be used. Also, any of the
pharmaceutically acceptable salts, esters, solvates, hydrates and
other derivatives that can deliver any of the drugs also can be
used, in any polymorphic forms, and combinations of any two or more
active ingredients can be used to prepare formulations. Although
many of the drugs are commonly formulated using their
pharmaceutically acceptable derivatives such as salts and esters,
for the sake of brevity only the base drugs have been listed.
[0048] Certain classes of drugs, such as analgesics, hypnotics,
drugs for treating bipolar disorder and schizophrenia, and other
drugs acting on the central nervous system, will desirably have a
rapid onset of action to provide more effective therapy. Enhancing
the rate of absorption of such drugs is particularly important when
they have low solubility, such as those drugs in BCS Classes II and
IV. In embodiments, the techniques disclosed herein will increase
the rates of drug dissolution in physiologic fluids.
[0049] Generally, the amount of drug in the compositions or
formulations of the present invention range from about 5% to about
75% of the total weight of the formulation. In some embodiments,
the amount of drug in the formulation ranges from about 20% to
about 50% by total weight of the formulation. In other embodiments,
the amount of drug in the formulation ranges from about 25% to
about 40% by total weight of the formulation. In yet further
embodiments, the amount of drug in the formulation ranges from
about 25% to about 30% by total weight of the formulation.
[0050] An aspect of the present disclosure includes intimate
mixtures of at least one amorphous drug substance and at least one
polymer. The term "intimate mixture" indicates that the components
are dispersions where the individual components are not
distinguishable using techniques such as optical microscopy, and
therefore cannot be simple mixtures of powdered components. In
embodiments, the dispersions can be considered solid dispersions,
molecular dispersions, or solid solutions of the components.
[0051] Suitable polymers for use in forming an intimate mixture
include, but are not limited to, ionic polymers, for example:
acrylics, such as various products of Evonik Industries, Germany,
sold as EUDRAGIT.TM. copolymers; polyvinyl acetate phthalates; and
the more hydrophobic cellulose ether derivatives, such as cellulose
acetate phthalates, hypromellose acetate succinates, and
hypromellose phthalates (e.g., in HP-50 and HP-55 grades).
Typically, the polymers are considered to be poorly water-soluble
or even insoluble in water, although they can degrade in fluids
having a weakly acidic, neutral, or basic pH, depending on the
polymer.
[0052] Without wishing to be bound by any particular theory, it is
believed that the ionic polymers assist in maintaining the drug or
active agent present in a substantially amorphous form, as that
term is defined herein. It is also believed, again without wishing
to be bound by any particular theory, that the dispersion or
intimate mixture of drug and ionic polymer provide for a glass
transition temperature between about 50.degree. C. and about
150.degree. C. In other embodiments, the dispersion may maintain a
glass transition temperature between about 50.degree. C. and about
100.degree. C. It is also believed that the use of an ionic
polymer, versus, for example, a non-ionic polymer, allows for
formulations which have a comparatively quicker disintegration
time, thus allowing for said compositions to be formulated as
orally disintegrating tablets.
[0053] The commercial product EUDRAGIT E 100 is a cationic
copolymer based on dimethylaminoethyl methacrylate, butyl
methacrylate, and methyl methacrylate, having a chemical name
"poly(butyl methacrylate-co-(2-dimethylaminoethyl)
methacrylate-co-methyl methacrylate) 1:2:1" and categorized in the
USP as "amino methacrylate copolymer."
[0054] EUDRAGIT L 100-55 is an anionic copolymer based on
methacrylic acid and ethyl acrylate, having a chemical name
"poly(methacrylic acid-co-ethyl acrylate) 1:1" and categorized in
the USP as "methacrylic acid copolymer, Type C."
[0055] EUDRAGIT L 100 is an anionic copolymer based on methacrylic
acid and methyl methacrylate, having a chemical name
"poly(methacrylic acid-co-methyl methacrylate) 1:1" and categorized
in the USP as "methacrylic acid copolymer, Type A."
[0056] EUDRAGIT S 100 is an anionic copolymer based on methacrylic
acid and methyl methacrylate, having a chemical name
"poly(methacrylic acid-co-methyl methacrylate) 1:2" and categorized
in the USP as "methacrylic acid copolymer, Type B."
[0057] Acrylic products are available in various physical forms,
for example, EUDRAGIT E PO being a powder form of EUDRAGIT E 100.
Polymer products similar to the EUDRAGIT products are commercially
available from other sources.
[0058] Hypromellose acetate succinate products are available from
Shin-Etsu Chemical Co. as AQOAT.TM. products, as well as from other
sources. They are mixtures of acetic acid and monosuccinic acid
esters of hydroxypropyl methylcellulose. The USP specification
requires that they contain from 12.0 to 28.0 percent of methoxy
groups, from 4.0 to 23.0 percent of hydroxypropyl groups, from 2.0
to 16.0 percent of acetyl groups, and from 4.0 to 28.0 percent of
succinoyl groups, calculated on the dry basis. For example, the
commercially available AQOAT AS-LF product contains 8% acetyl
groups and 15% succinoyl groups, the AQOAT AS-MF product contains
9% acetyl groups and 11% succinoyl groups, and the AQOAT AS-HF
product contains 12% acetyl groups and 7% succinoyl groups. Ionic
polymers have been widely used for enteric or delayed release
coating applications, and amorphous solid dispersion stabilization.
It has now been discovered that incorporation of ionic polymers
using the processes described below can produce orally fast
disintegrating tablets (ODT) of poorly soluble dugs with enhanced
bioavailability.
[0059] Various methods can be used to prepare intimate mixtures,
including combining the drug and polymer and melting the mixture.
Another useful method involves treating a solution of the drug and
polymer to form a solid mixture, such as by removing the solvent or
otherwise precipitating the solid mixture. Solvent may be removed
using techniques such as evaporation, for example under a vacuum in
a rotary evaporator or thin-film dryer, or by spray drying.
Precipitation also can involve combining the solution with an
anti-solvent or with another reagent that decreases the solubility
of the solutes, such as an aqueous acid. These and other
solubility-enhancing techniques are discussed below.
[0060] Technologies have been, and are continuing to be, developed
to improve the dissolution properties of poorly water-soluble
drugs, including, but not limited to, the following: salt
formation, use of more soluble "prodrug" compounds that form the
desired drug due to enzymatic or other chemical reactions within
the body, particle size reduction by attrition methods, solubilized
formulations, lipid-based formulations, emulsion systems, molecular
complexation, co-crystallization, and solid dispersions. Each of
these technologies aims to improve oral delivery of poorly-water
soluble drugs by increasing dissolution rates and/or enhancing
solubility.
[0061] Particle size reduction has been repeatedly demonstrated in
the pharmaceutical literature to significantly improve the
dissolution rates of poorly water-soluble drugs, correspondingly
yielding improved absorption and potentially improved drug
therapies. Approaches to particle size reduction can be categorized
as either "top-down" or "bottom-up" methods. Micronization, wet
milling and nano-milling are examples of techniques that can be
applied to poorly water-soluble drugs to reduce particle size by
top-down approaches. Controlled precipitation, evaporative
precipitation into aqueous solution, and micro-precipitation are
examples of methods for producing drug particles of reduced size by
bottom-up approaches.
[0062] In some embodiments, the particles have a size ranging from
between about 100 .mu.m to about 350 .mu.m. In other embodiments,
the particles have a size ranging from between about 100 .mu.m to
about 250 .mu.m.
[0063] Solid dispersion technology is a strategy for improving the
dissolution properties and hence oral bioavailability of poorly
water-soluble drugs. Solid dispersion technology involves
dispersing a poorly soluble drug in a solid polymer matrix. The
drug can exist in amorphous or crystalline form in the mixture,
which provides an increased dissolution rate and/or apparent
solubility in gastric and intestinal fluids. Several techniques
have been developed to prepare solid dispersions, including
co-precipitation, fusion, spray-drying, and hot melt extrusion.
Solid dispersion systems provide increased wettable drug particle
surface areas that significantly improve dissolution rates.
Therefore, the absorption of these compounds can be improved by
formulation as a solid dispersion system, if intestinal
permeability is not the limiting factor, i.e., BCS Class II
compounds.
[0064] In hot melt extrusion, a thermoplastic carrier polymer is
combined with a drug substance and optionally pharmacologically
inert excipients. The mixture is introduced into rotating screws
that convey the powder into a heated zone where shear forces are
imparted into the mixture, compounding the materials until a molten
mass is achieved. Hot-melt extrusion equipment includes an
extruder, auxiliary equipment for the extruder, downstream
processing equipment, and other monitoring tools used for
performance and product quality evaluation. The extruder is
typically composed of a feeding hopper, barrels, single or twin
screws, and the die and screw-driving unit. The auxiliary equipment
for the extruder mainly consists of a heating/cooling device for
the barrels, a conveyer belt to cool down the product and a solvent
delivery pump. The monitoring devices on the equipment include
temperature gauges, a screw-speed controller, an extrusion torque
monitor and pressure gauges.
[0065] The utilization of differently shaped dies and appropriate
downstream processing makes hot-melt extrusion a highly versatile
technology for the manufacture of a vast number of different dosage
forms. Films can be produced by extruding the material through
slit-shaped dies onto cooled rolls which stretch the film to the
targeted thickness. Extruded strands may be cut into tablets or
pelletized into short cylinders, which can then be spheronized to
obtain spherical particles. Cutting may be performed after cooling
of the strand on conveyer belts (strand pelletizers), or directly
upon extruder exit in the soft state (die-face pelletizers). In
addition to cutting operations, monolithic matrices may be obtained
by injection molding into tablet-shaped cavities or by calendaring
in the soft state between two counter-rotating calendar rolls.
Grinding of hot-melt extrudates yields powders which may be
directly compressed into tablets or used for dry powder coating
applications.
[0066] In spray-drying processes, a polymer and drug are first
dissolved in an organic solvent and then converted into a powdered
solid by atomization of the solution into small droplets and
vaporization of the solvent used with heated drying gas. Following
solvent evaporation, the dry powder particles are separated from
the gas with a filter or cyclone. Due to the large specific surface
area offered by the droplets, the solvent rapidly evaporates and
the solid dispersion is formed very rapidly, which may be fast
enough to prevent phase separation. The solid dispersions prepared
by spray drying consist of particles of which the size may be
customized by changing the droplet size to meet the requirements
for further processing or applications (e.g., free flowing
particles or particles for inhalation). Challenges associated with
spray-drying processes are related to the fact that both polymer
and drug have to be dissolved in an organic solvent to a high
solids content that remains sprayable. Also, processing conditions
have to be adjusted to avoid thermal stress of the product as well
as to yield a product with low level of residual solvents. The
advantages of using spray-dried process are related to one step
processing from liquid to powder form, quick drying, low thermal
stress of the drug, and high throughput rates.
[0067] Downstream processing of material prepared by a spray drying
process can involve blending of the obtained material with one or
more excipients, followed by compression into tablets. A
direct-compression process is influenced by the properties of the
excipients used such as surface energy and deformation. Further,
physico-mechanical properties of properly selected excipients to
ensure a robust and successful process include good flowability,
good binding functionality, good compressibility, low lubricant
sensitivity, and good machineability even in high-speed tableting
machinery with reduced dwell times.
[0068] A pH-controlled ionic precipitation (PCIP) relies on
solvent-controlled precipitation in acidic or basic aqueous
solution, therefore it is applicable only for ionic polymers (not
for water soluble polymers). PCIP processes include the following:
(a) dissolving the drug and ionic polymer in a suitable nonaqueous
solvent; and (b) contacting the solution of (a) with an aqueous
solution to produce a pH environment in which the ionic polymer is
poorly soluble, thereby microprecipitating the therapeutically
active compound and ionic polymer as a compound/polymer complex
wherein the therapeutically active compound is present in the
water-insoluble complex predominantly in amorphous form, as
determined by powder X-ray diffraction, and is present in the
complex at not less that about 10%, by weight, and the ionic
polymer is present in the compound/polymer complex at not less than
about 20%, by weight. In some embodiments, the pH of the aqueous
solution ranges from about 1 to about 4 for anionic polymers. In
other embodiments, the pH of the aqueous solution ranges from about
1 to about 3.5 for anionic polymers. In some embodiments, the pH of
the aqueous solution ranges from about 7 to about 11 for cationic
polymers. Downstream processing of material prepared by a PCIP
method can involve: (a) densification of the obtained material
using slugging or roller compaction processes; (b) milling of the
material from (a) to produce desired particle sizes; (c) blending
of milled material from (b) with one or more suitable excipients;
and (d) compression into tablets.
[0069] Fluid-bed coating utilizes a fluidized bed coating system,
wherein a solution containing a drug and a carrier is sprayed onto
particles of excipients, such as sugar or cellulose spheres, to
produce either granules ready for tableting or drug-coated pellets
for encapsulation in one step. This technique is based on removal
of the solvent from the bulk liquid, while the solid precipitates
and deposits on the surface of particles simultaneously. The
coating process is highly efficient and can be easily scaled up.
This method can be applied to both controlled- and
immediate-release solid dispersions.
[0070] Components of a solid dosage form include, but are not
limited to, one or more drug substances, together with any desired
number of excipients, such as diluents, binders, drug stabilizers,
disintegrants, glidants, lubricants, release rate modifiers,
anti-oxidants, coatings, colorants, sweeteners, flavoring agents,
etc.
[0071] Various useful fillers or diluents according to the present
application include, but are not limited to, starches, lactose,
cellulose derivatives, confectioner's sugar and the like. Different
grades of lactose include, but are not limited to, lactose
monohydrate, lactose DT (direct tableting), lactose anhydrous, and
others. Different starches include, but are not limited to, maize
starch, potato starch, rice starch, wheat starch, pregelatinized
starch, and others. Different celluloses that can be used include
crystalline celluloses, such as a microcrystalline cellulose, and
powdered celluloses. Other useful diluents include, but are not
limited to, carmellose, sugar alcohols such as mannitol, sorbitol,
and xylitol, calcium carbonate, magnesium carbonate, dibasic
calcium phosphate, and tribasic calcium phosphate.
[0072] Various useful binders according to the present application
include, but are not limited to, hydroxypropyl celluloses in
various grades, hydroxypropyl methylcelluloses in various grades,
polyvinylpyrrolidones in various grades, copovidones, powdered
acacia, gelatin, guar gum, carbomers, methylcelluloses,
polymethacrylates, and starches.
[0073] Various useful disintegrants include, but are not limited
to, carmellose calcium, carboxymethylstarch sodium, croscarmellose
sodium, crospovidone (crosslinked homopolymer of
N-vinyl-2-pyrrolidone), and low-substituted hydroxypropyl
celluloses. Other useful disintegrants include sodium starch
glycolate, colloidal silicon dioxide, alginic acid and alginates,
acrylic acid derivatives, and various starches.
[0074] In embodiments, formulations of the present application can
contain at least one antioxidant, for enhancing the stability of a
drug. The antioxidant may be present either as a part of a
formulation or as a packaging component. Antioxidants can be
present in amounts effective to retard decomposition of a drug that
is susceptible to oxidation. In embodiments, the content of an
antioxidant in the formulations ranges from about 0.001 to 10
weight percent, with respect to the active agent content.
Non-limiting examples of antioxidants include one or more of
ascorbic acid and its salts, tocopherols, sulfite salts such as
sodium metabisulfite or sodium sulfite, sodium sulfide, butylated
hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, and
propyl gallate. Other suitable antioxidants will be readily
recognized by those skilled in the art.
[0075] Useful lubricants include magnesium stearate, glyceryl
monostearates, palmitic acid, talc, carnauba wax, calcium stearate
sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc
stearate, polyoxyethylene monostearates, calcium silicate, silicon
dioxide, hydrogenated vegetable oils and fats, stearic acid, and
any combinations thereof.
[0076] One or more glidant materials, which improve the flow of
powder blends, pellets, etc. and help to minimize dosage form
weight variations, can be used. Useful glidants include, but are
not limited to, silicon dioxide, talc, kaolin, and any combinations
thereof.
[0077] Sweeteners that can be used include sucrose, sucralose,
aspartame, etc.
[0078] Useful flavoring agents include pharmaceutically acceptable
natural oils, natural flavors, and artificial flavors.
Representative flavors include, without limitation thereto,
menthol, peppermint, wintergreen, orange, cherry, and other fruits,
vanilla, almond and other nuts, etc. Mixtures of two or more
flavoring agents frequently are useful.
[0079] Coloring agents can be used to color code compositions, for
example, to indicate the type and dosage of the therapeutic agent
therein. Coloring agents can also be used to differentiate the
varied fractions of multi-particulates comprised in a unit dosage
form such as a capsule. Suitable coloring agents include, without
limitation, one or more natural and/or artificial colorants such as
FD&C coloring agents, natural juice concentrates, pigments such
as titanium oxide, silicon dioxide, iron oxides, zinc oxide, and
the like.
[0080] Various solvents that can be used in processes of preparing
pharmaceutical formulations of the present disclosure include, but
are not limited to, water, methanol, ethanol, acetone, diacetone,
polyols, polyethers, oils, esters, alkyl ketones, methylene
chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl
acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl
ether, diethylene glycol monobutyl ether, diethylene glycol
monoethyl ether, dimethylsulfoxide, N,N-dimethylformamide,
tetrahydrofuran, and any mixtures thereof.
[0081] The foregoing lists of excipient substances and processing
aids are not intended to be exhaustive, but are merely
representative of members of the various categories. Those skilled
in the art will be aware of many other useful substances, and their
use is specifically contemplated herein. Also, it is well-known
that many excipients can serve more than one function in
pharmaceutical formulations.
[0082] The following examples further describe certain specific
aspects and embodiments of the disclosure, and should not be
construed as limiting the scope of the disclosure in any manner. In
the examples, megestrol acetate is used as a representative for
poorly soluble drugs, but it will be apparent to those skilled in
the art that the disclosed techniques are also useful for many
other drug substances.
Example 1
[0083] Compositions were prepared using the ingredients and
temperatures listed below, where the numbers in parentheses for the
ingredients are weight percentages.
TABLE-US-00001 Composition Ingredients Temperature 1A Megestrol
acetate (40) 150-160.degree. C. Methacrylic acid copolymer, Type A*
(48) Triethyl citrate (12) 1B Megestrol acetate (40)
140-160.degree. C. Methacrylic acid copolymer, Type C** (60) 1C
Megestrol acetate (40) 120-140.degree. C. Hypromellose acetate
succinate*** (60) 1D Megestrol acetate (40) 140-150.degree. C.
Amino methacrylate copolymer**** (60) *e.g., EUDRAGIT L 100.
**e.g., EUDRAGIT L 100-55. ***e.g., AQOAT AS-LF. ****e.g., EUDRAGIT
E PO.
[0084] Ingredients were blended in a high-shear mixer and extruded
through a 2 mm die using a Leistritz NANO 16 piston-fed twin screw
extruder (Leistritz Extrusionstechnik GmbH, Nuremberg, Germany),
bottom feed mode, at the indicated temperatures. The extrudate was
then milled using a FitzMill Comminutor sold by The Fitzpatrick
Company, Elmhurst, Ill. U.S.A. (with screen #1521-0040, medium
speed, knife forward) and further characterized as described
below.
[0085] To evaluate physical stability of the extrudates, as well as
efficiency of the proposed process to convert crystalline megestrol
acetate to amorphous form, samples of the extrudates were placed in
20 mL amber glass containers and maintained open to the atmosphere
for one week at 40.degree. C. and 75% relative humidity ("RH"). The
physical form of the drug in the original extrudates and stored
samples was determined using X-ray powder diffraction, and results
are shown in FIGS. 1 and 2.
[0086] In the patterns of FIGS. 1 and 2, the x-axis is in degrees
2.theta. and the y-axis is intensity units. Curves A and D are
patterns for the starting megestrol acetate ingredient. Curve B is
for composition 1A, after storage for one week open to the
atmosphere at 40.degree. C. and 75% RH. Curve C is for initially
prepared composition 1A. Curve E is for composition 1D, after
storage for one week, open to the atmosphere at 40.degree. C. and
75% RH. Curve F is for initially prepared composition 1D. All X-ray
data presented herein are obtained using copper K.alpha.
radiation.
Example 2
[0087] Compositions were prepared to contain megesterol acetate
(40% by weight) and a polymer (60% by weight) using pH-controlled
ionic precipitation (PCIP). The drug and an anionic polymer were
dissolved in N,N-dimethylacetamide, to form solutions having 20% by
weight solute, and cold 0.1N hydrochloric acid is added until a
solid precipitates. The solid was separated and washed with 0.1N
HCl, then washed twice with cold water and dried overnight at room
temperature (25.degree. C.). The resulting powder was then passed
through a 40 mesh sieve and packaged for further use.
TABLE-US-00002 Composition Polymer 2A Methacrylic acid copolymer,
Type A* 2B Methacrylic acid copolymer, Type C** 2C Hypromellose
acetate succinate*** *e.g., EUDRAGIT L 100. **e.g., EUDRAGIT L
100-55. ***e.g., AQOAT AS-LF.
[0088] FIG. 3 shows X-ray diffraction patterns of the starting
megestrol acetate ("A") and samples prepared similarly to
composition 2A with the following varying drug to polymer weight
ratios: 50:50 ("B"); 40:60 ("C"); 35:65 ("D"); and 30:70 ("E").
X-axis units are degrees 2.theta. and the y-axis values are
intensity units. Without wishing to be bound by any particular
theory, it is believed that the crystallinity peaks for this drug
disappear when the polymer constitutes at least about 65 percent by
weight of the composition, but different drugs can become amorphous
using lower or higher amounts of polymer.
Example 3
[0089] Orally disintegrating tablet formulations 3A-3H were
prepared, using the ingredients in the table below.
TABLE-US-00003 mg per Tablet Ingredient 3A 3B 3C 3D 3E 3F 3G 3H
Megestrol acetate 125 125 125 125 125 125 125 125 Methacrylic acid
copolymer, 150 -- -- -- 150 -- -- -- Type A (EUDRAGIT L 100) Amino
methacrylate copolymer -- 187.5 -- -- -- 187.5 -- -- (EUDRAGIT E
PO) Methacrylic acid copolymer, -- -- 187.5 -- -- -- 187.5 -- Type
C (EUDRAGIT L 100-55) Hypromellose acetate succinate -- -- -- -- --
-- 187.5 (AQOAT AS-LF) Copovidone (KOLLIDON VA64) -- 187.5 Triethyl
citrate 37.5 -- -- -- 37.5 -- -- -- Crospovidone 73 73 73 15 15 73
73 15 Mannitol (PARTECK .TM. 100M) 130 130 130 45 45 130 130 45
Microcrystalline cellulose 120 120 120 67.5 67.5 120 120 67.5
(VIVAPUR .TM. 101) Sucralose 2 2 2 4 4 2 2 4 Peppermint flavor
powder -- -- -- 4 4 -- -- 4 Magnesium stearate 4 4 4 2 2 2 4 2
[0090] Procedure:
[0091] 1. Megestrol acetate and the required members of the next
five ingredients listed in the table were blended and extruded in a
manner similar to the extrusion of Example 1. The cooled extrudates
were passed through a FitzMill.TM. Comminutor having a 60 mesh
screen.
[0092] 2. Milled extrudates were blended with crospovidone,
mannitol, microcrystalline cellulose, sucralose and flavor (if
required), then magnesium stearate as added and blended.
[0093] 3. The blended materials were compressed into tablets, using
a force of about 8.9 kN (2000 pounds).
[0094] Tablets also were prepared using compositions prepared
according to the procedure of Example 2, substituting those
compositions for the milled extrudates in step 2, above.
[0095] Tablets prepared according to formulations 3A, 3D, 3E, and
3H above were tested for their disintegration times in water, using
the USP procedure. Results are shown in the table below.
TABLE-US-00004 Compo- Wt. Ratio of Disintegration sition Polymer
Drug to Polymer Time 3A EUDRAGIT L 100 40:60 5 seconds 3D KOLLIDON
VA64 25 minutes (Non-Ionic Polymer; Comparative Example) 3E
EUDRAGIT L100 20 seconds 3H AQOAT AS-LF 22 seconds
[0096] Tablets containing solid dispersions with ionic polymers
such as methacrylic acid copolymer, type A (e.g., EUDRAGIT L100) or
hypromellose acetate succinate (e.g., AQOAT AS-LF) disintegrate in
water rather quickly, i.e., in less than 30 seconds. By
optimization of tablet weights and certain excipient components,
disintegration times of tablets prepared with ionic polymers can be
further improved, to provide disintegration times from 20 seconds
to 5 seconds. However, tablets containing solid dispersions
prepared with water-soluble nonionic polymers, such as copovidone,
disintegrate fairly slowly as demonstrated by the disintegration
time of 25 minutes for composition 3D.
[0097] Although the present disclosure should not be bound to any
particular theory of operation, it is possible that tablets
containing an amorphous drug embedded in a poorly water-soluble
ionic polymer will quickly disintegrate due to the slow hydration
properties of the ionic polymer in water. Solid dispersions
prepared with a water-soluble nonionic polymer (e.g., copovidone)
might disintegrate more slowly due to rapid hydration properties of
the nonionic polymer in water, which hinders its disintegration and
consequently retards the drug release.
[0098] Dissolution testing of compositions 3D and 3H as performed
using USP apparatus 2 and 900 mL of 10 mM phosphate buffer (pH
6.8), with 50 rpm rotation. Results are shown in FIG. 4, where the
x-axis is minutes and the y-axis is the cumulative percentage of
contained drug that dissolves. Curve A is for composition 3H and
curve B is for composition 3D. As shown in FIG. 4, the dissolution
profile of a composition containing a solid drug dispersion with a
poorly water-soluble ionic polymer (composition 3H) exhibits rapid
drug release, which could be due to the rapid dosage form
disintegration. The composition containing a solid drug dispersion
prepared with a water-soluble non-ionic polymer (composition 3D)
exhibits slower drug release, which could be due to relatively
slower disintegration properties of the dosage form.
[0099] Solubility testing was conducted, by combining 200 mg of a
drug-containing uncompressed final blend composition with 100 mL of
50 mM phosphate buffer (pH 7.5) and placing the mixture in a closed
container on a shaker apparatus. Samples (2 mL each) are withdrawn
at intervals and analyzed for their dissolved megestrol acetate
concentration using ultraviolet spectrophotometry. Results are
shown in FIG. 5, where the x-axis is minutes and the y-axis is the
drug concentration in mg/mL. Curve A is for composition 3H, curve B
is for composition 3A, curve C is for composition 3G, and curve D
is for the starting megestrol acetate ingredient.
Example 4
[0100] Orally disintegrating tablets were prepared, using the
procedure described in Example 3 and the ingredients in the
following table.
TABLE-US-00005 mg per Tablet Ingredient 4A 4B 4C 4D Megestrol
acetate 62.5 187.5 62.5 187.5 Hypromellose acetate succinate 250
125 -- -- (AQOAT AS-LF) Copovidone (KOLLIDON VA64) -- -- 250 125
Crospovidone 15 15 15 15 Mannitol (PARTECK 100M) 45 45 45 45
Microcrystalline cellulose 67.5 67.5 67.5 67.5 (VIVAPUR 101)
Sucralose 4 4 4 4 Peppermint flavor powder 4 4 4 4 Magnesium
stearate 2 2 2 2
[0101] The tablets were tested for their disintegration times in
water, using the USP procedure, and results are shown below.
TABLE-US-00006 Compo- Wt. Ratio of sition Polymer Drug to Polymer
Disintegration Time 4A AQOAT AS-LF 20:80 40 seconds 4B Ionic
Polymer 60:40 2 minutes, 36 seconds 4C KOLLIDON 20:80 37 minutes,
12 seconds 4D VA64 60:40 35 minutes Non-Ionic Polymer (Comparative
Example)
[0102] As shown in the table, tablets containing solid dispersions
with a poorly water-soluble ionic polymer, e.g., hypromellose
acetate succinate (AQOAT AS-LF) disintegrate in water significantly
faster than tablets containing solid dispersions with a
water-soluble nonionic polymer, e.g., copovidone (KOLLIDON
VA64).
Example 5
[0103] Orally disintegrating tablets were prepared, using the
procedure described below and the ingredients in the following
table.
TABLE-US-00007 mg per Tablet Ingredient 5A 5B 5C Ziprasidone base
30 -- -- Eszopiclone -- 3 -- Sumatriptan Succinate -- -- 30 Citric
acid 10 -- -- Eudragit EPO 100 10 100 Crospovidone 15 10 15
Mannitol (PARTECK 100M) 15 40 15 Microcrystalline cellulose 15 33
15 (VIVAPUR 101) Sucralose 6 2 6 Peppermint flavor powder 2 1 2
Magnesium stearate 2 1 2
[0104] Procedure:
[0105] 1. The drug and Eudragit EPO were blended in the PK blender
and extruded in a manner similar to the extrusion of Example 1. The
cooled extrudates were passed through a FitzMill.TM. comminutor
having a 60 mesh screen.
[0106] 2. Milled extrudates were blended with crospovidone,
mannitol, microcrystalline cellulose, sucralose and flavor, then
magnesium stearate is added and blended.
[0107] 3. The blended materials were compressed into tablets.
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