Note: Descriptions are shown in the official language in which they were submitted.
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DOSAGE FORMS HAVING IMPROVED RELEASE PROPERTIES
Related Application
This application is a continuation-in-part of U.S. application Serial No.
08/946,065, filed October 7, 1997.
Field of the Invention
The invention relates to dosage forms containing pharmaceutically active
agents
and having superior in vitro and in vivo characteristics when compared to
conventional
products. The tablets contain thermoformed particulates containing active
agents along
with a variety of pharmaceutical additives, including optional coatings .
Background of the Invention
For several types of pharmaceutical products, e.g., anticholesterolemics such
as
lovastatin, the attainment of a high CMAX (highest plasma concentration at any
point in
time) and large A. U . C . (total amount of drug absorbed as measured by the
area under
the curve of a plot of plasma concentration vs. time) is desirable. However,
the poor
solubilities of lovastatin and other agents of its type make attainment of
these goals
problematic.
The invention deals with dosage forms which use binary particulates,
preferably
microspheres, containing only active agents) and solubilizing agents) . The
particulates are dry, solid dispersions made by subjecting the active and
solubilizing
ingredients to liquiflash conditions to directly produce microspheres or non-
spherical
particulates. When they contain certain amounts of solubilizing agents, the
particulates
are used in products that give higher CMAX and A.U.C. values when ingested
than
products that do not contain the same types and amounts of solubilizers.
Melt blends of active agents with solubilizers such as surfactants have been
previously disclosed.
U. S. Patent 4,944,949 discloses micelles of non-steroidal anti-inflammatory
drugs (NSAIDS) with nonionic surfactants such as poloxamers (col. 5, line 31).
Micelles are aggregates in which surfactant molecules are arranged in a
spheroidal
structure, with the hydrophobic regions at the core and the hydrophilic
regions at the
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other surfaces. Drugaurfactant ratios of 1:5.7 to 1:50 are disclosed at column
12, line
57.
U. S. Patent 5,281,420 shows tebufelone, an anti-inflammatory agent, in solid
dispersions containing 15 % to 75 % tebufelone and 25 % to 65 % of a poloxamer
surfactant (col. 1, lines 35-51).
U. S. Patent 5,525,353 deals with laxative: compositions which contain
poloxamer surfactants, as stool softeners, melt-bL~nded with stimulants. The
ratio of
surfactant to stimulant is 2:1 to 20:1 (col. 2, line 22+). The compositions
are
administered in hard gelatin capsules.
EPO Application 0 317 780, published May 31, 1989, shows quick-release and
sustained-release formulations containing dihydropyridine calcium channel
blockers and
poloxamer surfactants. The quick release compositions contain 0.15:1 to 0.5:1
of
hydroxypropylmethylcellulose to dihydropyridine/poloxamer complex (p. 6, 1. 48-
49).
The complex contains 1:1 to 1:10 ratios of drug to surfactant (page 6, lines
25-27).
In publications dated 1994 and 1997, BASF Corporation discloses melt extruded
drug/polymer products. But details of their preparation are not disclosed.
W097/02017, published January 23, 199!7, discusses oral dosage forms which
contain a solid dispersion of an active ingredient: in a poloxamer polymer.
The ratio of
active agent to poloxamer is 0.1:1.0 to 10.0:1.0 (page 3, line 280.
U. S. Patent 4,727,109 shows liquid preparations containing an active agent
and
a carrier system consisting of a hydrophilic component, a hydrophobic
component and a
solubilizer. The hydrophilic component may be: a polyethylene glycol or a
polyoxyethylene/polyoxypropylene copolymerizate. See column 2, lines 35-44.
U. S. Patent 5,456,923 describes solid dispersions of drugs in polymers made
by
extruding the two together and pulverizing the extrudate.
Polyoxyethylene/polyoxypropylene copolymers are disclosed at column 3, lines
33-34,
as plasticizers.
U. S. Patent 5,292,461 deals with pellets produced by spraying an active agent
with a wetting agent. Polyethylene glycols are disclosed as lubricants (column
7, line
62) and agents which influence the release of tlhe active ingredient (column
8, lines 1-2).
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Poloxamers are recited as surface-active agents (c:olumn 7, line 65).
The art has not successfully blended polymeric solubilizing agents with
actives
to directly produce stable) dry particulates, notably microspheres, of uniform
size.
Summary of the Invention
The invention is concerned with particulates containing only active agents and
solubilizers, and with dosage forms, e.g., capsule;s and tablets, made
therefrom as well
as with thermoforming processes for making these dosage fornns.
Dosage forms of the invention can contain thermoformed particulates along with
pharmaceutical additives. These dosage forms, such as caplets, capsules and
tablets, are
highly stable and give improved in vitro solubility/-dissolution and in vivo
performance
for the active agents) therein, relative to delivery of the same active
agents) without
the microspheres. Oral dosage forms are typical.
When spherical, the particulates of the invention are readily flowable, so
that
processing and delivery to the consumer are facilitated, regardless of the
type of product
in which they are used.
Detailed Description of the Invention
Unless otherwise stated, all percentages recited herein are weight percentages
based on total composition weight.
The particulates of this invention are made by subjecting at least one active
and
at least one solubilizer to thermoforming techniques, e.g. liquiflash
processing or
extrusion.
Liquiflash and flash flow techniques for making microspheres are known in the
art. One process uses the apparatus disclosed in U. S. Serial No. 08/874,215,
filed
June 13, 1997. The liquiflash process is also described in
U. S. Patent 5,683,720. The disclosures of both are incorporated herein by
reference.
U. S. Patents 5,445,769 and 5,458,823 show devices which can be used to make
liquiflash microspheres. These disclosures are also incorporated herein by
reference. .
In addition, extrusion mixing can be used to make the particulates of the
invention. In some preferred embodiments, the active ingredients) and
polymeric
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solubilizer(s) are combined in suitable ratios to yield eutectic mixtures or
other
drug/solubilizer mixtures.
Feedstocks
Particulates used in the invention are made from binary feedstocks which are
either spheronized using liquiflash techniques or made into particulates using
other
thermoforming processes. The feedstocks contain, as the only ingredients:
(a) about 5 % to about 80 % of at least one active ingredient, and
(b) about 95 % to about 20 % of at least one polymeric solubilizing agent.
Drug/solubilizer combinations containing; about 10 % to about 95 % active, and
preferably 30 % to about 90 % active and most preferably about 40 to about 80
% active
are useful in making particulates in general . Combinations containing about
20 % to
40 % active agent and about 80 % to 60 %a solubilizer are highly effective in
making
microspheres. Non-spherical particulates preferably contain drug: solubilizer
ratios of
about 60:40 to about 75:25. In some cases excEas solubilizer is used, so that
the active
is enveloped or coated by the solubilizer.
The active ingredients useful herein can be selected ftom a large group of
therapeutic agents. Respective classes include those in the following
therapeutic
categories: ace-inhibitors; alkaloids; antacids; ;analgesics; anabolic agents;
anti-allergy
agents; anti-anginal drugs; anti-arrhythmia agents; antiasthmatics;
antibiotics;
anticholesterolemics; anticonvulsants; anticoagulants; antidepressants;
antidiarrheal
preparations; anti-emetics; antihistamines; antihypertensives; anti-
infectives; anti-
inflammatories; antilipid agents; antimanics; anti-migraine agents;
antinauseants;
antipsychotics; antistroke agents; antithyroid preparations; anabolic drugs;
antiobesity
agents; antiparasitics; antipsychotics; antipyretics; antispasmodics;
antithrombotics;
antiiumor agents; antitussives; antiulcer agents; anti-uricemic agents;
anxiolytic agents;
appetite stimulants; appetite suppressants; beta-blocking agents;
bronchodilators;
cardiovascular agents; cerebral dilators; chelating agents; cholecystekinin
antagonists;
chemotherapeutic agents; cognition activators; contraceptives; coronary
dilators; tough _
suppressants; decongestants; deodorants; dermatological agents; diabetes
agents;
diuretics; emollients; enzymes; erythropoietic drugs; expectorants; fertility
agents;
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fungicides; gastrointestinal agents; growth regulaitors; hormone replacement
agents;
hyperglycemic agents; hypoglycemic agents; ion-exchange resins; laxatives;
migraine
treatments; mineral supplements; mucolytics) narcotics; neuroleptics;
neuromuscular
drugs; non-steroidal anti-inflammatories (NSAIDs); nutritional additives;
peripheral
vasodilators; polypeptides; prostaglandins; psychotropics; renin inhibitors;
respiratory
stimulants; sedatives; steroids; stimulants; sympatholytics; thyroid
preparations;
tranquilizers; uterine relaxants; vaginal preparations; vasoconstrictors;
vasodilators;
vertigo agents; vitamins; wound healing agents; .and others.
Active agents which may be used in the invention include: acetaminophen;
acetic
acid; acetylsalicylic acid, including its buffered forms; acrivastine;
albuterol and its
sulfate; alcohol; alkaline phosphatase; allantoin; aloe; aluminum acetate,
carbonate,
chlorohydrate and hydroxide; alprozolam; amino acids; aminobenzoic acid;
amoxicillin;
ampicillin; amsacrine; amsalog; anethole; ascorbic acid; aspartame;
astemizole;
atenolol; azatidine and its maleate; bacitracin; balsam peru; BCNU
(carmustine);
beclomethasone diproprionate; benzocaine; ben~:oic acid; benzophenones;
benzoyl
peroxide; benzquinamide and its hydrochloride; bethanechol; biotin; bisacodyl;
bismuth subsalicylate; bornyl acetate; bromophE:niramine and its maleate;
buspirone;
caffeine; calamine; calcium carbonate, casinate arid hydroxide; camphor;
captopril;
cascara sagrada; castor oil; cefaclor; cefadroxil; cephalexin; centrizine and
its
hydrochloride; cetyl alcohol; cetylpyridinium chloride; chelated minerals;
chloramphenicol; chlorcyclizine hydrochloride; chlorhexidine gluconate;
chloroxylenol;
chloropentostatin; chlorpheniramine and its maleates and tannates;
chlorpromazine;
cholestyramine resin; choline bitartrate; chondrogenic stimulating protein;
cimetidine
and its hydrochloride; cinnamedrine hydrochloride; citalopram; citric acid;
clarithromycin; clemastine and its fumarate; clonidine and its hydrochloride
salt;
clorfibrate; cocoa butter; cod liver oil; codeine. and its fumarate and
phosphate; _
cortisone acetate; ciprofloxacin HCI; cyanocob~alamin; cyclizine
hydrochloride;
cyproheptadine and its hydrochloride; danthron; dexbromopheniramine maleate;
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dextromethorphan and its hydrohalides; diazepam; dibucaine;
dichloralphenazone;
diclofen and its alkali metal sales; diclofenac sodium; digoxin;
dihydroergotamine and
its hydrogenates/mesylates; diltiazem; dimethicone; dioxybenzone;
diphenhydramine
and its citrate; diphenhydramine and its hydrochloride; divalproex and its
alkali metal
salts; docusate calcium, potassium, and sodium; doxycycline hydrate;
doxylamine
succinate; dronabinol; efaroxan; enalapril; enoxacin; ergotamine and its
tartrate;
erythromycin; estropipate; ethinyl estradiol; ephedrine; epinephrine
bitartrate;
erythropoietin; eucalyptol; famotidine; fenoprofen and its metal salts;
ferrous fumarate,
gluconate and sulfate; fluoxetine; folic acid; fosphenytoin; 5-fluorouracil (5-
FU);
fluoxetine and its hydrochloride; furosemide; gabapentan; gentamicin;
gemflbrozil;
glipizide; glycerine; glyceryl stearate; granisetron and its hydrochloride;
griseofulvin;
growth hormone; guafenesin; hexylresorcinol; hydrochlorothiazide; hydrocodone
and
its tartrates; hydrocortisone and its acetate; 8-hydroxyquinoline sulfate;
hydroxyzine
and its pamoate and hydrochloride salts; ibuprofen; indomethacin; inositol;
insulin;
iodine; ipecac; iron; isosorbide and its mono- and dinitrates; isoxicam;
ketamine;
kaolin; ketoprofen; lactic acid; lanolin; lecithin; leuprolide acetate;
lidocaine and its
hydrochloride salt; lifinopril; liotrix; loratadine; lovastatin; luteinizing
holmore; LHRH
(lutenizing hormone replacement hormone); magnesium carbonate, hydroxide,
salicylate, and trisilicate; meclizine and its hydrochloride; mefenamic acid;
meclofenamic acid; meclofenamate sodium; medroxyprogesterone acetate;
methenamine
mandelate; menthol; meperidine hydrochloride; metaproterenol sulfate;
methscopolamine and its nitrates; methsergide and its maleate; methyl
nicotinate;
methyl salicylate; methyl cellulose; methsuximide; metoclopramide and its
halides/hydrates; metronidazole and its hydrochloride; metoprotol tartrate;
miconazole
nitrate; mineral oil; minoxidil; morphine; naproxen and its alkali metal
sodium salts;
nifedipine; neomycin sulfate; niacin; niacinamide; nicotine; nicotinamide;
nitroglycerine; nonoxynol-9; norethindrone and its acetate; nystatin;
octoxynol;
octoxynol-9; octyl dimethyl PABA; octyl metlaoxycinnamate; omega-3
polyunsaturated
fatty acids; omeprazole; ondansetron and its hydrochloride; oxolinic acid;
oxybenzone;
oxtriphylline; para-aminobenzoic acid (PABA); padimate-O; paramethadione;
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_'7_
pentastatin; peppermint oil; pentaerythritol tetranitrate; pentobarbital
sodium;
perphenazine; phenelzine sulfate; phenindamine and its tartrate; pheniramine
maleate;
phenobarbital; phenol; phenolphthalein; phenylephrine and its tannates and
hydrochlorides; phenylpropanolamine and its hydrochloride salt; phenytoin;
pirmenol;
piroxicam and its salts; polymicin B sulfate; potassium chloride and nitrate;
prazepam;
procainamide hydrochloride; procaterol; promethazine and its hydrochloride;
propoxyphene and its hydrochloride and napsylate; pramiracetin; pramoxine and
its
hydrochloride salt; prochlorperazine and its maleate; propanolol and its
hydrochloride;
promethazine and its hydrochloride; propanolol; pseudoephedrine and its
sulfates and
hydrochlorides; pyridoxine; pyrolamine and its hydrochlorides and tannates;
quinapril;
quinidine gluconate and sulfate; quinestrol; ralitoline; ranitadine;
resorcinol; riboflavin;
salicylic acid; scopolamine; sesame oil; shark liver oil; simethicone; sodium
bicarbonate ) citrate, and fluoride; sodium monofluorophosphate; sucralfate;
sulfanethoxazole; sulfasalazine; sulfur; sumauiF~tan and its succinate;
tacrine and its
hydrochloride; theophylline; terfenadine; thieth;~lperazine and its maleate;
timolol and
its maleate; thioperidone; trimetrexate; triazolaln; tretinoin; tetracycline
hydrochloride;
tolmetin; tolnaftate; triclosan; trimethobenzamide and its hydrochloride;
tripelennamine
and its hydrochloride; tripolidine hydrochloride:; undecylenic acid;
vancomycin;
verapamil HCI; vidaribine phosphate; vitamins A, B, C, D, B,, B2, B6, B,z, E,
and K;
witch hazel; xylometazoline hydrochloride; zinc; zinc sulfate; zinc
undecylenate.
Mixtures and pharmaceutically acceptable salts of these and other actives can
be used.
Particularly useful active agents are sparingly soluble solid agents whose
dissolution and release properties are enhanced. by the solubilizing agents
used herein.
These agents include H2 antagonists, analgesics, including non-steroidal anti-
inflammatory drugs (NSAIDs), anticholesterolemics, anti-allergy agents and
anti-
migraine agents.
H2-antagonists which are contemplated for use in the present invention include
cimetidine, ranitidine hydrochloride, famotidine, nizatidine, ebrotidine,
mifentiditie, -
roxatidine, pisatidine and aceroxatidine.
Analgesics include aspirin, acetaminophen, acetaminophen plus caffeine, and
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_g_
non-steroidal anti-inflammatory drugs (NSAIDS),,, e.g.) aspirin and ibuprofen.
Useful NSAIDs include ibuprofen; diclofenac and its alkali metal salts;
fenoprofen and its metal salts; ketoprofen, naproxen and its alkali metal
salts; and
piroxicam and its salts.
Anticholesterolemics include a wide variety of liquid lowering agents. Among
them are bile acid sequestrants, HMG-CoA reductose inhibitors, and statins, e.
g.,
lovastatin, provastatin and the like.
Useful anti-allergy agents include hydricodone and its tartrates; clemastine
and
its fumarate; azatadine and its maleate; acetaminophen; hydroxyzine and its
pamoate
and hydrochloride salts; chlorpheniramine and its maleates and tannates;
pseudoephedrine and its sulfates and hydrochlorides; bromopheniramine and its
maleate; dextromethorphan and its hydrohalides; loratadine; phenylephrine and
its
tannates and hydrochlorides; methscopolamine and its nitrates;
phenylpropanolamine
and its hydrochlorides; codeine and its hydrochloride; codeine and its
phosphate;
terfenadine; acrivastine; astemizole; cetrizine ar.~d its hydrochloride;
phenindamine and
its tartrate; tripelennamine and its hydrochloride; cyproheptadine and its
hydrochloride;
promethazine and its hydrochloride; and pyrilarnine and its hydrochlorides and
tannates.
Useful antimigraine agents include divalproex and its alkali metal salts;
timolol
and its maleate; propanolol and its hydrohalides; ergotanune and its tartrate;
caffeine;
sumatriptan and its succinate; dihydroergotamine, its hydrogenates/mesylates;
methsergide and its maleate; isometheptene mucate; and dichloralphenazone.
Another class of drugs which can be used are antiemetics. Useful antiemetics
include: meclizine and its hydrochloride; hydroxyzine and its hydrochloride
and
pamoate; diphenhydramine and its hydrochloride; prochlorperazine and its
maleate;
benzquinamide and its hydrochloride; granisetlon and its hydrochloride;
dronabinol;
bismuth subsalicylate; promethazine and its hydrochloride; metoclopramide and
its
halides/hydrates; chlorpromazine; trimethobenzamide and its hydrochloride;
thiethylperazine and its maleate; scopolamine; perphenazine; and ondansetron
and.its _
hydrochloride.
Other active ingredients for use in the present invention include
antidiarrheals
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such as immonium AD, antihistamines, antitussives, decongestants, vitamins,
and
breath fresheners. Also contemplated for use herein are anxiolytics such as
Xanax;
antipsychotics such as clozaril and Haldon; antihistamines such as Seldane,
Hismanal,
Relafen, and Tavist; antiemetics such as Kytril and Cesamet; bronchodilators
such as
Bentolin, Proventil; antidepressants such as Proz;ac, Zoloft, and Paxil;
antimigranes
such as Imigran, ACE-inhibitors such as Vasotec:, Capoten and Zestril; Anti-
Alzheimers
agents such as Nicergoline; and Call-Antagonists such as Procardia, Adalat,
and Calan.
Combinations of various types of drugs, as well as combinations of individual
drugs, are contemplated.
The solubilizing agents, or solubilizers, used herein are commercially
available
hydrophilic surfactants. One group of useful solubilizers are diblock
copolymers
containing only polyoxyethylene units and polyoxypropylene units, termed
"poloxamers." Poloxamers having polyoxy-ethylene and polyoxypropylene block
segments are very useful, and those with about 60 % to about 90 % , and
particularly
about 70 % to about 80 % , polyoxyethylene units are notable . Suitable
polymers are
sold under "Lutrol", "Monolan" and "Pluronic" trade names (BASF). Poloxamer
188
("Pluronic F68") is very effective. It contains .80 polyoxyethylene units and
27
polyoxypropylene units ) with an average molecular weight of about 7680 to
9510. See
Handbook of Pharmaceutical Excipients, 2nd edition, (1994) pages 352-354,
which
disclosure is hereby incorporated by reference.
Other useful "Pluronic" polymers include those designated as F87, F108, F127
and F237.
Another group of solubilizers are polyethylene glycol esters sold under the
"Gelucire" name (Gattefosse). "Gelucire 50/13", a polyethylene glycol-32
glyceryl
palmitostearate ester (HLB 13) is useful.
The Process of Making Particulates
Thermoforming techniques useful in making the particulates of the invention
include liquiflash and extrusion processing.
Liauiflash Processing
Liquiflash processing involves providing the ingredients at a particle size of
less
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than 1 ~tM. Milling/grinding may be necessary preliminary steps. The particles
are
then blended and used as a feedstock for a suitable device wherein heat and
pressure
conditions are controlled to effect morphological changes in the feedstock.
Inside the device, the feedstock particles lose their resistance to liquid
flow and
go into a "liquiform" state. In this state, particles of the material, or a
substantial
portion thereof, are physically transformed from their original solid state,
through a
liquid state, and back to a solid state instantaneously . While the particles
undergo this
transformation, they are acted upon by centrifugal force, or another shearing
force,
which force separates them into discrete spherical particles, i. e.,
microspheres. This is
termed "spheronization" . The transformed particles exit the device as
discrete
microspheres of about 10 microns to about 600 microns, and generally about 50
to
about 300 microns particle diameter.
U. S. Patents 5,445,769 and 5,458,823, .and application Serial Nos. 08/330,412
and 08/874,215, set out the details of the liquiflash and flash flow
spheronization
processes. Their disclosures are incorporated herein by reference.
Extrusion Processing
Extrusion techniques to be used in the invention include those in which the
temperatures range from those at or below which a drug/solubilizer eutectics
form to
those at or below which the active ingredients) melt or readily dissolve in
the
solubilizer(s). One exemplary technique employs ibuprofen/Pluronic F68
combinations
and temperatures of about 35°C to about 45°C.
Extruders, flash flow spinning heads, and the like are useful devices.
The particulates may be ground or reduced in size by other means.
Dosage Forms
The particulates can be used as is, e.g., in powders, sachets and the like, or
as
ingredients in other dosage forms, such as caplets, capsules, and tablets.
Such dosage
forms can contain the microspheres or other pa.rticulates described herein and
one or
more conventional pharmaceutical additives. - -
The microspheres are optionally coated with suitable amounts of one or more -
pharmaceutical coatings. Conventional coatinl;s include taste-masking
coatings, enteric
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coatings and the like. The coatings may not significantly alter the
dissolution and
release properties of the product. Cellulosic coatings, in sutiable amounts,
are
contemplated. Suitable amounts and types of exci.pients, e.g., fillers,
flavors, flow
control agents, lubricants, perfumes, can be blended with the microspheres
before or
during preparation of a final dosage form.
When the microspheres are used to make tablets, the concentrations of tablet
ingredients will fall into the ranges shown in Table 1.
Table 1. Tablet Ingredients
BROAD NARROW
INGREDIENT RANGE (%) RANGE (%)
PARTICULATES 50 - 70 55 - 60
SOLID DILUENT(S)20 - 40 30 - 35
DISINTEGRANT(S)3 - 5 3 - 4
GLIDANT(S) 2 - 5 2 - 3
LUBRICANTS) 2 - 5 2 - 3
OTHER ADDITIVES0 - 10 0 - 5
The solid diluent is generally a bulking .agent. It is typically present a
weight
concentration which is ll2 to 2/3 of the concentration of micr0spheres.
Useful solid diluents are microcrystalline cellulose products having mean
particle sizes of about 20 microns to about 180 microns. The Avicel products,
especially Avicel PH101 (FMC) are effective.
Disintegrants may assist in the release of the active agent after ingestion of
the
dosage form. Useful disinte-grants include croscarmellose sodium,
polyvinylpyrrolidone (PVP), sodium starch giycolate and mixtures thereof. "Act-
Di-
Sol" , a croscarmellose sodium product made b~y FMC, is very useful, as is
Kollidon
CL-M, a crospovidone (BASF).
One or more glidants such as starch, talc, lactose, stearates and colloidal
silica
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can be used. "Cab-o-sil M5" , a brand of colloidal silica made by Cabot, is
very useful .
Lubricants are used in the tablet compositions, among them stearic acid and
its
esters, adipic acid, fatty acid esters, talc, magnesium stearate, mineral oil
and the like
and mixtures thereof. Magnesium stearate is highly effective.
Other conventional pharmaceutical additives and coatings can be employed.
Mixing Procedures
The microspheres are mixed with the other tablet composition ingredients using
conventional equipment.
Tablets were made on a rotary tablet press, such as a Stokes or Kilian rotary
tablet press.
Examples
The following examples illustrate the invE:ntion:
Example I
Lovastatin Microspheres
Lovastatin powder and milled Polaxamer 188 in a ratio of 5:95 were placed in a
Stephan mixer in the following order: (1) one-half of the solubilizing agent,
(2) all of
the lovastatin, (3) the remaining portion of the solubilizing agent. The
ingredients were
mixed for about five minutes and used as a feedstock, as follows:
The feedstock was fed to the 5-inch spinning head disclosed in U. S.
Application
Serial No. 08/874,215, filed June 13, 1997. The head speed was increased to
60Hz
while the heating elements were raised to a temperature which produced
liquiflash
conditions (about 60°C to 90°C).
The spinning head forced the material tluough the screen and the product vas _
permitted to free fall a distance of from six to Eight feet below the head.
The product
consists of binary microspheres containing lovastatin and a solubilizer and
having a
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highly consistent particle size, with diameters of about 100 microns to about
400
microns .
Example II
Lovastatin Microspheres
Using a procedure similar to that used in Example I, microspheres containing
20:80 and 40:60 lovastatinaolubilizing agent were prepared. Poloxamer 188 was
used.
Example III
Lovastatin Dissolution Studies
The 40:60 lovastatinaolubilizer microspheres were tested using the standard in
vitro dissolution test procedure of USP App. II at 50 rpm, 900 mL dissolution
buffer,
pH 7.0 with 2 % sodium lauryl sulfate, with the following dissolution profile:
Table 2a. Dissolution of Lovastatin Microspheres
TIME PERCENT
(MINUTES) DISSOLVED
88
98
100
101*
45 101*
6p 101*
*theoretical
For comparison, a dissolution study was run on 20 mg tablets of "Mevacor, " a
commercial lovastatin preparation (Merck). This product contains lovastatin,
cellulose, .
lactose, magnesilun stearate, starch and butylated hydroxyanisole. See
Phvsician's
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Desk Reference, 51st ed. (1997), p. 1742, incorporated herein by reference.
Using the test procedure described above, the "Mevacor" tablets exhibited the
following dissolution profile:
Table 2b. Dissolution of Commercial Tablets
TIME :PERCENT
(MINUTES) DISSOLVED
30
66
86
90
45 92
Clearly, the microspheres of the invention dissolved faster than the
commercial
formulation. Eighty-eight percent (88 % ), 98 % , and 100 % of the lovastatin
in the
microspheres dissolved in 5 minutes, 10 minutea, and 20 minutes, respectively,
compared to 30 % , 66 % , and 86 % dissolution f or the commercial product at
the same
time points.
Table 3. Lovastastin Aqueous Solubility
--_
AQUEOUS
PRODUCT SOLUBILITY
(ug/mL)
RAW DRUG MATERIAL 3.94
5/95 LOVASTATIN/PLURONIC :F68 15.43
10/90 LOVASTATIN/PLURONIC'. F68 16.43
20/80 LOVASTATIN/PLURONIC', F68 18.47
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These values were derived by placing a 11~ mg drug equivalent sample in 100
mL water in a beaker and stirring overnight. The solution made is tested by
HPLC to
determine the concentration of drug therein.
Example I'V
Lovastatin Bioavailability Study
In in ultra bioavailability tests, gelatin capsules containing microspheres
made
using the invention gave superior plasma profiles to those obtained using the
commercial lovastatin tablet. The study protocol was designed to determine
mevinolinic acid concentrations in blood samples taken at various points in
time.
Mevinoiinic acid is a metabolite associated with lovastatin use.
Abstract of Bioavailability Protocol
Name of Samples: Immediate-release lovastatin and Mevacor~
Active Ingredients: Lovastatin USP
Study Dosage: 4x20mg tablets, Mevacor (Merck & Co.)
Immediate-Release: Lovastatin 4x20mg capsules, 20:80
Lovastatin:Pluronic.
Objective: Determine the single-dose; bioavailability of an investigational
formulation of immediate-release lovastatin relative to
Mevacor~
Population: Healthy, nonsmoking mate and female human volunteers, 40 to
70 years of age, inclusive.
Study Design: Single center, randomized, open label, 3-way crossover design -
3
treatments, 3 periods lasting approximately 3 days each;
minimum 7-day washout.
Sample Size: 9 subjects.
Sample Analysis: Serum mevinolinic acid.
Primary Variables: Serum mevinolinic acid C""x, Tm,x and
AUCo.
Blood Samples: Pre-dose and 0.5.) 1, 1,5, 2, 3, 4, 5, 6, 8, 10, 12, and 24
hours after dosing. - -
The results are shown in the following table:
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Table 4. Plasma Concentrations of Mevinolinic Acid over Time
MEVOLINIC ACID (ng/mL)
MEVACOR LOVASTATIN
HOURS
LOW - HIGH LOW - HIGH
0.0 0.00 - 0.00 0.00 - 0.00
0.5 0.1 - 0.963 0.00 - 0.00
1 0.185 - 11.6 0.00 - 0.979
1.5 0.277 - 19'.3 0.00 - 6.26
2 0.729 - 24..6 0.287 - 5.96
3 0.508 - 29.4 1.83 - 32.8
4 0.820 - 27.7 2.26 - 36.6
0.845 - 211.2 2.33 - 36.8
6 1.31-14.7 1.57-33.6
8 1.43 - 9.80 1.27 - 19.6
0.749-9.09 0.918- 17.2
12 0.350 - 4.99 0.443 - 8.31
18 0.158-3.51 0.146-8.32
24 0.113 - 2..38 0.128 - 5.67
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Table 5. Pharmacokinelic Parameters
MEVACOR LOVASTATIN
PARAMETERS MEAN (SD) MEAN (SD)
CMAX (ng~~-) 9.89 (8.13) 12.7 (10.1)
TMAX (~') 4.60 (2.3) 5.1 (0.78)
A. U . C . (0-last) 72. 6 (60. 8;) 92.9 (97 .4)
*
* 82.0 (71.4) 118 (153)
A.U.C. (0-infj
*expressed as ng/hr/mL
Reasonable variations, such as those which would occur to a skilled artisan,
can
be made herein without departing from the scope: of the invention.
