U.S. patent application number 09/925348 was filed with the patent office on 2002-03-28 for solid pharmaceutical dosage formulation of hydrophobic drugs.
Invention is credited to Chen, Jen-Chi, Chrai, Suggy S., Kadare, Ashok, Karetny, Marc S., Murari, Ramaswamy, Parry, Gregory E..
Application Number | 20020036154 09/925348 |
Document ID | / |
Family ID | 22839969 |
Filed Date | 2002-03-28 |
United States Patent
Application |
20020036154 |
Kind Code |
A1 |
Murari, Ramaswamy ; et
al. |
March 28, 2002 |
Solid pharmaceutical dosage formulation of hydrophobic drugs
Abstract
A novel solid pharmaceutical dosage formulation of hydrophobic
drugs is disclosed, which provides enhanced dissolution and
improved bioavailability. The formulation comprises: a base
substrate comprising a first polymer; a deposit, comprising a
therapeutic amount of a hydrophobic drug, deposited on the base
substrate; a cover substrate comprising a second polymer, the cover
substrate covering the deposit and joined to the base substrate by
a bond that encircles the deposit; and a dissolution-enhancing
amount of a surfactant, disposed within a carrier that is
segregated from, but in contact with, the deposit. In another
embodiment, the dosage form may include any pharmaceutically
acceptable additive, disposed within a carrier that is segregated
from, but in contact with, the deposit. In a preferred embodiment,
the hydrophobic drug is deposited electrostatically on the base
substrate.
Inventors: |
Murari, Ramaswamy;
(Hillsborough, NJ) ; Chrai, Suggy S.; (Cranbury,
NJ) ; Chen, Jen-Chi; (Morrisville, PA) ;
Kadare, Ashok; (Highland Park, IL) ; Parry, Gregory
E.; (Lawrenceville, NJ) ; Karetny, Marc S.;
(Langhorne, PA) |
Correspondence
Address: |
ALLEN BLOOM
C/O DECHERT
PRINCETON PIKE CORPORATION CENTER
P.O. BOX 5218
PRINCETON
NJ
08543-5218
US
|
Family ID: |
22839969 |
Appl. No.: |
09/925348 |
Filed: |
August 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60224275 |
Aug 10, 2000 |
|
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|
Current U.S.
Class: |
206/538 |
Current CPC
Class: |
A61K 9/2095 20130101;
A61K 9/2086 20130101; A61K 9/7007 20130101 |
Class at
Publication: |
206/538 |
International
Class: |
B65D 083/04; B65D
085/42 |
Claims
We claim:
1. An improved solid pharmaceutical dosage formulation of a
hydrophobic drug, comprising: a base substrate comprising a first
polymer; a deposit, comprising a therapeutic amount of a
hydrophobic drug, deposited on the base substrate; a cover
substrate comprising a second polymer, the cover substrate covering
the deposit and joined to the base substrate by a bond that
surrounds the deposit; and a dissolution-enhancing amount of a
surfactant, disposed within a carrier that is segregated from, but
in contact with, the deposit.
2. The dosage formulation of claim 1, wherein the base substrate
comprises a planar film.
3. The dosage formulation of claim 1, wherein the cover substrate
comprises a planar film.
4. The dosage formulation of claim 3, wherein the cover substrate
film has a shape comprising a semi-spherical bubble, wherein the
deposit is disposed within the perimeter of the semi-spherical
bubble.
5. The dosage formulation of claim 2, wherein the base substrate
film has a shape comprising a semi-spherical bubble, wherein the
deposit is disposed within the perimeter of the semi-spherical
bubble.
6. The dosage formulation according to claim 1, wherein the deposit
has a shape that is substantially circular, and the deposit has a
diameter in the range of about 3 millimeters to about 7
millimeters.
7. The dosage formulation according to claim 1, wherein the first
polymer or second polymer comprises a thermoplastic material.
8. The dosage formulation according to claim 1, wherein the first
polymer or second polymer is selected from the group consisting of
polymers and copolymers of polyvinyl alcohol, polyvinyl
pyrrolidinone, polysaccharide polymers, acrylate polymers,
methacrylate polymers, phthalate polymers, polyvinyl acetate,
methyl cellulose, carboxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulo- se, ethyl
cellulose, polyethylene oxide, polypropylene, polyester and
polyamide films, Eudragits, starch-based polymers and gelatin.
9. The dosage formulation according to claim 1, wherein the first
polymer and the second polymer are the same.
10. The dosage formulation according to claim 1, wherein the base
substrate and the cover substrate are ingestible.
11. The dosage formulation according to claim 1, wherein the
carrier is the cover substrate.
12. The dosage formulation according to claim 1, wherein the
carrier is an ingestible adhesive that is applied to the cover
substrate.
13. The dosage formulation according to claim 1, wherein the
carrier is a pouch, disposed between the deposit and the cover
substrate, the pouch comprising an ingestible material.
14. The dosage formulation according to claim 1, wherein the
hydrophobic drug is deposited electrostatically.
15. An improved solid pharmaceutical dosage formulation,
comprising: a base substrate comprising a first polymer; a deposit,
comprising a therapeutic amount of a drug, deposited on the base
substrate; a cover substrate comprising a second polymer, the cover
substrate covering the deposit and joined to the base substrate by
a bond that surrounds the deposit; and a pharmaceutically
acceptable additive, disposed within a carrier that is segregated
from, but in contact with, the deposit.
16. The dosage formulation according to claim 15, wherein the drug
is deposited electrostatically.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to improved solid
pharmaceutical dosage forms. In particular, the present invention
is concerned with enhancing the dissolution of hydrophobic
drugs.
[0002] Hydrophobic Drugs
[0003] As is well known, many pharmaceutically active compounds
intended for oral administration are poorly soluble in water.
Hydrophobic drugs do not generally dissolve easily and rapidly in
the gastro-intestinal tract. This hydrophobic property often makes
it difficult to formulate a drug so that it exhibits a satisfactory
bioavailability profile in vivo. Poor bioavailability may lead to
ineffective therapy, the need for higher dosing and/or undesirable
side effects.
[0004] It has been recognized that the addition of a surfactant
during the processing of a hydrophobic drug may improve the
dissolution of the dosage units within the gastro-intestinal tract.
Furthermore, for some hydrophobic drugs, the addition of a
surfactant during processing may improve the bioavailability of the
product due to improved wetting of the hydrophobic active
ingredient, leading to faster dissolution and absorption.
[0005] Therefore, in order to compensate for the poor solubility of
certain hydrophobic drugs, various carrier systems have been
suggested wherein such drugs are co-formulated in intimate
admixture with certain surfactants and other ingredients.
[0006] For example, U.S. Pat. No. 4,344,934 discloses a mixture or
solution of a poorly water-soluble drug with a pharmaceutically
acceptable water-soluble polymer, wherein said mixture or solution
has been treated with a minor amount of a wetting agent selected
from anionic and cationic surfactants. Such compositions are formed
as follows: First, a mixture or solution of the drug with the
water-soluble polymer is formed. The mixture can be formed in a
solvent or solvent mixture which is a mutual solvent for both the
drug and the polymer. After the drug-polymer mixture or solution
has been formed in a solvent, it is dried by spray-drying, flash
evaporation or air drying. The powdered drug-polymer mixture is
then treated with an amount of a primarily aqueous wetting solution
containing a wetting agent selected from anionic and cationic
surfactants. The treated mixture is then again dried and, if
necessary, it is milled, screened or ground prior to formulating
into suitable dosage forms with pharmaceutically acceptable
excipients.
[0007] U.S. Pat. No. 5,827,541 discloses a process for the
preparation of an oral, rapidly disintegrating dosage form of a
hydrophobic drug. The process comprises forming a suspension of the
hydrophobic drug in a solvent containing a pharmaceutically
acceptable surfactant together with a water-soluble or
water-dispersible carrier material; forming discrete units of the
suspension; and removing solvent from the discrete units under
conditions whereby a network of the carrier material carrying a
dosage of the hydrophobic drug is formed.
[0008] Thus, the common approach known in the art tends to focus on
the development of carrier systems wherein the hydrophobic drug
must be intimately admixed with the surfactant and other
components. A serious disadvantage of this approach is that it has
required the development, more or less empirically, of a separate
carrier system for each hydrophobic drug. Also, admixing of
wetting/solubilizing agents with the active ingredient can lead to
product instability due to interaction between the drug and the
wetting/solubilizing agent. The necessity to devise a separate
carrier system for each drug is, of course, time-consuming and
expensive. There continues to be a need for a single drug carrier
system which is suitable for a wide range of different hydrophobic
drugs.
[0009] Deposition of Drugs
[0010] A unique type of solid dosage form may be obtained by
deposition of an active pharmaceutical ingredient on a
pharmaceutically acceptable substrate. Various means for depositing
pure active ingredients, such as weighing, spraying or spreading,
can be used to generate the dosage form as taught, for example, in
the following patents and patent publications, the disclosures of
which are incorporated by reference herein in their entireties:
U.S. Pat. Nos. 5,845,463, 5,240,049, 5,018,335 and 4,640,322, as
well as WO 00/09249, SU 1803328 and GB 2238768.
[0011] In a preferred embodiment, electrostatic deposition
methodologies can be used. In the electrostatic deposition process,
a cloud or stream of charged particles of the active ingredient is
exposed to, or directed towards, a substrate, at the surface of
which substrate a pattern of opposite charges has been established.
In this fashion, a measured dosage of the active ingredient can be
adhered to the substrate. Preferred electrostatically deposited
dosage forms are disclosed in published international patent
application number WO 99/63972, assigned to the assignee of the
present invention, the disclosure of which is incorporated by
reference herein in its entirety.
[0012] Although electrostatic drug deposition generally has certain
benefits, including improved dose uniformity, certain problems
still arise when the drug to be electrostatically deposited is
hydrophobic. Specifically, the final dosage form may suffer from
the same problems of poor dissolution and poor bioavailability that
were discussed above with respect to conventional solid dosage
forms of hydrophobic drugs. Moreover, the prior art approach,
involving the intimate admixture of the hydrophobic drug and a
surfactant, would be difficult or impossible to implement in the
context of electrostatic deposition.
[0013] For example, if the drug and surfactant powders are to be
blended prior to electrostatic deposition on the substrate, it may
be difficult to obtain a suitably homogenous blend, or to maintain
such homogeneity during the charging and delivery to the substrate.
Moreover, co-deposition of two different powders would require that
both powders behave similarly during the deposition, but this is
difficult to achieve since different powders often have different
optimum deposition parameters. In an extreme case, the surfactant
may deposit only under a charge opposite that utilized for the
active ingredient.
[0014] One possible solution would be to deposit the active
ingredient and the surfactant sequentially. However, there may be
difficulty in forming depositions on top of pre-existing
depositions, due to charge dissipation.
[0015] Therefore, it would be desirable to provide a dosage form of
a hydrophobic drug, wherein the problems of poor solubility and
poor bioavailability, as well as the technical problems identified
in the preceding paragraphs, are overcome.
SUMMARY OF THE INVENTION
[0016] In accordance with the teachings of the present invention,
improved solid pharmaceutical dosage formulations are provided,
characterized by the enhanced dissolution of hydrophobic drugs. The
formulations comprise:
[0017] a base substrate comprising a first polymer;
[0018] a deposit, comprising a therapeutic amount of a hydrophobic
drug, deposited on the base substrate;
[0019] a cover substrate comprising a second polymer, the cover
substrate covering the deposit and joined to the base substrate by
a bond that surrounds the deposit; and
[0020] a dissolution-enhancing amount of a surfactant, disposed
within a carrier that is segregated from, but in contact with, the
deposit.
[0021] It is accordingly an object of the present invention to
provide solid pharmaceutical dosage formulations of hydrophobic
drugs having enhanced dissolution and improved bioavailability.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 depicts an isometric view of a product comprising a
strip package containing a plurality of unit forms in accordance
with the prior art.
[0023] FIG. 2 depicts a cover layer of a prior art strip package
partially separated from a substrate.
[0024] FIG. 3 depicts a side view of an illustrative unit form in
accordance with the prior art.
[0025] FIG. 4 depicts a top view of the illustrative unit form of
FIG. 3.
[0026] FIG. 5 depicts components of various embodiments of unit
forms of the present invention.
[0027] FIG. 6 is a graph of dissolution profiles for the drug
CCN00401.
[0028] FIG. 7 is a graph of dissolution profiles for the drug
hydrocortisone.
[0029] FIG. 8 is a graph of dissolution profiles for the drug
glipizide.
DETAILED DESCRIPTION OF THE INVENTION
[0030] FIGS. 1 through 4 depict the general structure of prior art
dosage forms which are to be improved in accordance with the
present invention. In FIG. 1, product 1 comprises a package 2 that
is realized as a strip 4 having an array of unit dosage forms 6.
Strip 4 comprises a substrate 8 and a cover layer 9.
[0031] Substrate 8 and cover layer 9 each comprise a substantially
planar, flexible film or sheet. In some embodiments, one of either
substrate 8 or cover layer 9 includes an array of semi-spherical
bubbles, concavities, blisters or depressions (hereinafter
"bubbles") 12 that are advantageously arranged in columns and rows.
In the illustrative package depicted in FIG. 1, cover layer 9
comprises a three-by-five array of such bubbles 12, although more
or fewer bubbles may suitably be provided. Substrate 8 and cover
layer 9 are advantageously formed to have a thickness of about
0.001 inches (0.0254 mm) and typically comprise a thermoplastic
material. Materials suitable for use as substrate 8 and/or cover
layer 9 include, without limitation, polymers and copolymers of
polyvinyl alcohol, polyvinyl pyrrolidinone, polysaccharide
polymers, acrylate polymers, methacrylate polymers, phthalate
polymers, polyvinyl acetate, methyl cellulose,
carboxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose, ethyl
cellulose, polyethylene oxide, polypropylene, polyester and
polyamide films, Eudragits (that is, polymers and copolymers
containing methacrylic acid), starch-based polymers, gelatin and
the like. Polyvinyl alcohol films suitable for use as the substrate
and/or cover layer are commercially available from Polymer Films,
Inc. of West Haven, Conn.; Chris Craft of Gary, Ind.; Aquafilm of
Winston-Salem, N.C.; Idroplast S.p.A. of Montecatini Terme (PT),
Italy; Aicello Chemical Co., Ltd. of Toyohashi; Japan; and Soltec
of Paris, France.
[0032] As depicted in FIG. 2 (showing cover layer 9 partially
"peeled" back from substrate 8) and FIG. 3, a deposit of a dry
active ingredient 14, in the form of powder(s)/grains (hereinafter,
"powder") is disposed between substrate 8 and cover layer 9 within
a bubble 12. Active ingredient 14 is deposited on substrate 8. As
depicted via a cross-sectional view in FIG. 3 and plan view in FIG.
4 (each showing only a single bubble 12), substrate 8 and cover
layer 9 are attached to one another via bonds or welds 7 that are
near to and encircle bubble 12. Bonding can be effected, for
example, via heat or ultrasonic welding or via suitable adhesives.
Unit form 6 comprises a deposit of active ingredient 14, bubble 12,
and a region of substrate 8 within bonds 7. Unit form 6 is a stable
"core" (hereinafter, an "Accudep.TM. Core"), which may be further
processed into a dosage form resembling a conventional tablet,
capsule, caplet and the like or processed into a non-conventional
wafer or stamp-like presentation. The preferred dosage forms may be
suitable for oral, transdermal or buccal dosing of appropriate
drugs.
[0033] Suitable means of electrostatic deposition of active
ingredient 14 are described in, for example, U.S. Pat. Nos.
5,714,007, 5,846,595 and 6,074,688, the disclosures of which are
incorporated by reference herein in their entireties. In addition
to the electrostatic powder cloud deposition method, active
ingredient may be coated onto the substrate in the form of a
solution or a suspension of finely divided medicament; e.g., a
collodial suspension. The liquid utilized for these operations can
be water, an organic solvent, e.g., ethanol, or a hydroalcoholic
solvent. One method of loading active ingredient in a liquid form
onto a substrate is by electrostatic jet spray deposition. In this
method, the active ingredient containing solution or suspension is
metered into an apparatus which projects a spray of microdroplets
which are concentrated on a particular area of the substrate
through the use of a defined area electrostatic field.
[0034] In addition to electrostatic jet spray deposition, certain
other coating techniques recognized in other arts as being amenable
to the coating of a substrate with a liquid may be utilized in
loading a pharmaceutically acceptable substrate with active
ingredient. For example, the substrate may be passed under a roll
which is immersed in a bath of saturating fluid. As the substrate
passes the roller, the excess fluid is "wiped" from the substrate
by another roller, a jet of air, a rubber wiping bar, a wire-wound
rod, e.g., a Meier rod, or the like.
[0035] The present invention improves upon the prior art dosage
forms depicted in FIGS. 1 through 4 by providing a
dissolution-enhancing amount of a surfactant, disposed within a
carrier that is segregated from, but in contact with, the active
ingredient. The invention is based on the surprising finding that,
contrary to the teachings in the prior art, a surfactant can
improve the dissolution (and, consequently, the bioavailability) of
a hydrophobic drug even though the drug and the surfactant are not
co-formulated in intimate admixture with one another.
[0036] Certain embodiments of the present invention are depicted in
FIG. 5. In the drawing with the legend "Deposition," active
ingredient ("drug") 14 is shown after being deposited on substrate
8, prior to sealing with cover layer 9. In the first drawing with
the legend "Cover Film" ("Surfactant in Pouch"), the surfactant is
incorporated on the cover layer ("cover film") 9 in a pouch 16, and
cover layer 9 is aligned to place the pouch 16 in contact with
active ingredient 14. The pouch material may be any polymer, and
preferably the same material as substrate 8 or cover layer 9. Upon
administration of the dosage form, during dissolution of cover
layer 9 and/or substrate 8, pouch 16 similarly dissolves and
releases the surfactant in the immediate vicinity of the drug,
thereby improving drug dissolution.
[0037] An alternative embodiment of the present invention is
depicted in the second drawing in FIG. 5 with the legend "Cover
Film" ("Surfactant in Adhesive"). In this embodiment, the
surfactant is incorporated in an ingestible adhesive 10 that is
applied to cover layer 9. After sealing cover layer 9 to substrate
8, the surfactant is in contact with, but segregated from, active
ingredient 14. Upon administration of the dosage form and
dissolution of cover layer 9 and/or substrate 8, the adhesive
dissolves and releases the surfactant in the immediate vicinity of
the drug, again improving drug dissolution.
[0038] In a preferred embodiment (not specifically shown in FIG.
5), neither a pouch 16 nor a special adhesive 10 is required.
Rather, the surfactant is incorporated directly in cover layer 9,
so that the dissolving cover layer 9 releases the surfactant in the
immediate vicinity of the encapsulated hydrophobic drug, allowing
the surfactant to interact with the drug to help with
dissolution.
[0039] In the context of the present invention, "hydrophobic drug"
means a drug that ranges from "sparingly soluble" to "practically
insoluble or insoluble," as shown in the following table:
1 Parts of Solvent Required Descriptive Term For 1 Part of Solute
Sparingly soluble From 30 to 100 Slightly soluble From 100 to 1000
Very slightly soluble From 1000 to 10,000 Practically insoluble, or
Insoluble 10,000 and over
[0040] The hydrophobic drugs, and their pharmaceutically acceptable
salts, which may be formulated in accordance with the present
invention include, without limitation, the following:
[0041] Analgesics and anti-inflammatory agents: acetaminophen,
aloxiprin, auranofin, azapropazone, benorylate, celecoxib,
diflunisal, etodolac, fenbufen, fenoprofen, flurbiprofen,
ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic
acid, nabumetone, naproxen, oxyphenbutazone, phenylbutazone,
piroxicam, rofecoxib, salicylamide, salicylic acid, sulindac.
[0042] Anthelmintics: albendazole, bephenium hydroxynaphthoate,
cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine,
oxantel embonate, oxfendazole, praziquantel, pyrantel embonate,
thiabendazole.
[0043] Anti-arrhythmic agents: amiodarone, disopyramide,
flecainide, quinidine.
[0044] Anti-bacterial agents: benethamine, cefaclor, cinoxacin,
ciprofloxacin, clarithromycin, clofazimine, cloxacillin,
demeclocycline, doxycycline, erythromycin, ethionamide, imipenem,
nalidixic acid, nitrofurantoin, penicillin, rifampicin, spiramycin,
sulphabenzamide, sulphacetamide, sulphadiazine, sulphadoxine,
sulphafurazole, sulphamerazine, sulphamethoxazole, sulphapyridine,
tetracycline, trimethoprim.
[0045] Anti-coagulants: dicoumarol, dipyridamole, nicoumalone,
phenindione.
[0046] Anti-depressants: amoxapine, maprotiline, mianserin,
nortriptyline, oxypertine, trazodone, trimipramine.
[0047] Anti-diabetics: acetohexamide, chlorpropamide,
glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide.
[0048] Anti-epileptics: beclamide, carbamazepine, clonazepam,
ethotoin, metharbital, methoin, methsuximide, methylphenobarbitone,
oxcarbazepine, paramethadione, phenacemide, phenobarbitone,
phensuximide, phenytoin, primidone, sulthiame, valproic acid.
[0049] Anti-fungal agents: amphotericin, butoconazole,
clotrimazole, econazole, fluconazole, flucytosine, griseofulvin,
itraconazole, ketoconazole, miconazole, natamycin, nystatin,
sulconazole, terbinafine, terconazole, tioconazole, undecenoic
acid.
[0050] Anti-gout agents: allopurinol, probenecid,
sulphinpyrazone.
[0051] Anti-hypertensive agents: amlodipine, benidipine,
darodipine, diazoxide, dilitazem, felodipine, guanabenz,
isradipine, methyldopa, minoxidil, nicardipine, nifedipine,
nimodipine, phenoxybenzamine, prazosin, reserpine, terazosin.
[0052] Anti-malarials: amodiaquine, chloroquine, chlorproguanil,
halofantrine, mefloquine, proguanil, pyrimethamine, quinine.
[0053] Anti-migraine agents: dihydroergotamine, ergotamine,
methysergide, pizotifen, sumatriptan.
[0054] Anti-muscarinic agents: atropine, benzhexol, biperiden,
ethopropazine, hyoscyamine, mepenzolate, oxyphencylcimine,
tropicamide.
[0055] Anti-neoplastic agents and immunosuppressants:
aminoglutethimide, amsacrine, azathioprine, busulphan,
chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide,
finasteride, lomustine, melphalan, mercaptopurine, methotrexate,
mitomycin, mitotane, mitozantrone, procarbazine, raloxifene,
tamoxifen, testolactone.
[0056] Anti-Parkinsonian agents: bromocriptine, lysuride.
[0057] Anti-protazoal agents: benznidazole, clioquinol,
decoquinate, diiodohydroxyquinoline, diloxanide, dinitolmide,
furzolidone, metronidazole, nimorazole, nitrofurazone, omidazole,
tinidazole.
[0058] Anti-thyroid agents: carbimazole, propylthiouracil.
[0059] Anxiolytics, sedatives, hypnotics and neuroleptics:
allobarbitone, allylbarbituric acid, alprazolam, amylobarbitone,
barbitone, bentazepam, bromazepam, bromperidol, brotizolam,
butobarbitone, carbromal, carphenazine, chlordiazepoxide,
chlormethiazole, chlorpromazine, clobazam, clotiazepam, clozapine,
cyclobarbitone, diazepam, droperidol, ethinamate, flunanisone,
flunitrazepam, fluopromazine, flupenthixol, fluphenazine,
flurazepam, haloperidol, lorazepam, lormetazepam, medazepam,
meprobamate, methaqualone, midazolam, nitrazepam, oxazepam,
pentobarbitone, perphenazine, pimozide, prochlorperazine,
sulpiride, temazepam, thioridazine, triazolam, zopiclone.
[0060] .beta.-Blockers: acebutolol, alprenolol, atenolol,
labetalol, metoprolol, nadolol, oxprenolol, pindolol,
propranolol.
[0061] Cardiac Inotropic agents: amrinone, digitoxin, digoxin,
enoximone, lanatoside C, medigoxin.
[0062] Corticosteroids: beclomethasone, betamethasone, budesonide,
cortisone, desoxymethasone, dexamethasone, flucortolone,
fludrocortisone, flunisolide, fluticasone, hydrocortisone,
methylprednisolone, prednisolone, prednisone, triamcinolone.
[0063] Diuretics: acetazolamide, amiloride, amisometradine,
bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone,
ethacrynic acid, furosemide, hydrochlorothiazide, metolazone,
spironolactone, triamterene.
[0064] Gastro-intestinal agents: aminosalicylic acid, bisacodyl,
cimetidine, cisapride, diphenoxylate, domperidone, famotidine,
loperamide, mesalazine, nizatidine, omeprazole, ondansetron,
ranitidine, sulphasalazine.
[0065] Histamine H.sub.1-Receptor Antagonists: acrivastine,
astemizole, cinnarizine, cyclizine, cyproheptadine, dimenhydrinate,
fexofenadine, flunarizine, loratadine, meclozine, oxatomide.
[0066] Lipid-regulating agents: atorvastatin, bezafibrate,
clofibrate, dextrothyroxine, fenofibrate, gemfibrozil, lovastatin,
probucol, simvastatin.
[0067] Nitrates and other anti-anginal agents: amyl nitrate,
glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate,
pentaerythritol tetranitrate.
[0068] Nutritional agents: betacarotene, vitamin A, vitamin B,
vitamin D, vitamin E, vitamin K.
[0069] Opioid analgesics: codeine, dextropropyoxyphene,
diamorphine, dihydrocodeine, meptazinol, methadone, morphine,
nalbuphine, pentazocine.
[0070] Respiratory agents: montelukast, pranlukast (CCN00401),
zafirlukast, zileuton.
[0071] Sex hormones: clomiphene, conjugated estrogens, danazol,
estradiol, ethinyloestradiol, medrogestone, medroxyprogesterone
acetate, mestranol, methyltestosterone, norethisterone,
norgestimate, norgestrel, progesterone, stanozolol, stiboestrol,
testosterone, tibolone.
[0072] Stimulants: amphetamine, cocaine, dexamphetamine,
dexfenfluramine, fenfluramine, mazindol.
[0073] Thyroid agents: levothyroxine.
[0074] By "surfactant" is meant, for purposes of the present
invention, that the material is a surface active agent which
displays wetting, detergent or soap-like qualities as those agents
are understood by those of ordinary skill in the art. Thus, the
term "surfactant," as used herein, represents ionic and nonionic
surfactants or wetting agents commonly used in the formulation of
pharmaceuticals, such as ethoxylated castor oil, benzalkonium
chloride, polyglycolyzed glycerides, acetylated monoglycerides,
sorbitan fatty acid esters, poloxamers, polyoxyethylene fatty acid
esters, polyoxyethylene derivatives, monoglycerides or ethoxylated
derivatives thereof, diglycerides or polyoxyethylene derivatives
thereof, sodium docusate, sodium lauryl sulfate, magnesium lauryl
sulfate, triethanolamine, cetrimide, sucrose laurate and other
sucrose esters, glucose (dextrose) esters, simethicone, ocoxynol,
dioctyl sodium sulfosuccinate, polyglycolyzed glycerides, sodium
dodecylbenzene sulfonate, dialkyl sodium sulfosuccinate, fatty
alcohols such as lauryl, cetyl, and steryl, glycerylesters, cholic
acid or derivatives thereof, lecithins, and phospholipids.
[0075] The surfactants of the invention may be classified by an
"HLB number." The HLB number provides a means for ranking
surfactants based on the balance between the hydrophilic and
lipophilic portions of the surfactant. That is, the higher the HLB
number, the more hydrophilic the surfactant.
[0076] In a broader implementation of the present invention, many
other types of pharmaceutical additives (instead of, or in addition
to, the surfactant) may be included in the dosage form disposed
within a carrier that is segregated from, but in contact with, the
deposited active ingredient. Such pharmaceutically acceptable
additives include, but are not limited to, antioxidants,
antimicrobial agents, complexing agents, acidity boosting agents,
alkalinity boosting agents, buffering agents, carrier molecules,
chelating compounds, preservatives and the like. "Pharmaceutically
acceptable" here means that the additive may be introduced safely
into the human or animal body, for example, taken orally and
digested. Examples of such additives include, but are not limited
to, the following:
[0077] Acidifying agents: citric acid, maleic acid, lactic acid,
malic acid, succinic acid, tartaric acid.
[0078] Alkalinity buffering agents: calcium carbonate,
monoethanolamine, potassium citrate, sodium bicarbonate, sodium
citrate, triethanolamine.
[0079] Anti-microbial agents: benzethonium chloride, benzoic acid,
bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol,
chlorocresol, cresol, editic acid, ethylparaben, glycerol,
imidurea, methylparaben, phenol, phenolic acid, phenoxyethanol,
phenyl ethyl alcohol, phenylmercuric salts (acetate, borate and
nitrate), potassium sorbate, propylene glycol, propylparaben,
sodium benzoate, sodium propionate, sorbic acid, thimerosol.
[0080] Anti-oxidants: alpha tocopherol, ascorbic acid, ascorbic
acid palmitate, butylated hydroxyanisole, fumaric acid, malic acid,
propyl gallate, sodium ascorbate, sodium metabisulfate.
[0081] Complexing agents: EDTA, potassium citrate, sodium
citrate.
EXAMPLES
[0082] The following materials were used in the Examples:
[0083] Hydroxypropylmethylcellulose E50 ("HPMC"), available from
Dow Chemical Company, Midland, Mich.
[0084] Hydroxypropylcellulose JFP ("HPC"), available from Hercules
Inc., Wilmington, Del.
[0085] Polyethylene Glycol 400 ("PEG"), available from Union
Carbide Corporation, Danbury, Conn.
[0086] Sodium lauryl sulfate ("SLS"), HLB=40, available from
Spectrum Quality Products, New Brunswick, N.J.
[0087] Polysorbate 80 (Tween 80), HLB=15, available from Uniqema, a
division of ICI, Wilmington, Del.
[0088] Polysorbate 20 (Tween 20), HLB=16.7, available from
Uniqema
[0089] Hydrocortisone, available from Spectrum Quality Products
[0090] Glipizide, available from Fine Chemicals Corporation,
Capetown, South Africa.
Example 1
[0091] A model compound, CCN00401, was used to test the effect
sodium lauryl sulfate (SLS) has on dissolution of an Accudep.TM.
Core. Several types of Accudep.TM. Cores were made as follows:
[0092] Control Accudep.TM. Core: Sealed a 1 mg deposition of
CCN00401 between two polymer sheets with the following composition:
45% HPMC, 45% HPC, 10% PEG.
[0093] SLS incorporated in film Accudep.TM. Core: Sealed a 1 mg
deposition of CCN00401 between two polymer sheets with the
following composition: 33.75% HPMC, 33.75% HPC, 7.5% PEG, 25% SLS
(equivalent of about 1.2 mg SLS incorporated in each Accudep.TM.
Core).
[0094] SLS mixed directly with CCN00401 Accudep.TM. Core: Sealed
mixture of 2 mg of CCN00401/SLS mixture (50/50) between two polymer
sheets with the following composition: 45% HPMC, 45% HPC, 10%
PEG.
[0095] Dissolution profiles for the Accudep.TM. Cores listed above
were generated under the following conditions: 50 rpm, paddles, pH
8.0 TRIS buffer. In addition, a set of Control Accudep.TM. Cores
were tested in dissolution media that also contained Polysorbate
20.
[0096] FIG. 6 shows the average dissolution profiles for all the
CCN00401 dissolution runs (n=3). As seen in FIG. 6, the addition of
SLS in the polymer film or mixed directly with the drug led to
significantly faster dissolution at 15 minutes (even faster than
the case where Polysorbate 20 is present in the media). At 30
minutes all experimental sets had average dissolution in the
mid-to-high 90% range except for the case with no surfactant in
Accudep.TM. Core or dissolution media.
Example 2
[0097] Hydrocortisone, CCN90306A, was used to test the effect SLS
and Polysorbate 80 have on dissolution of an Accudep.TM. Core.
Accudep.TM. Cores were made as follows:
[0098] Control Accudep.TM. Core: Sealed a 1 mg deposition of
CCN90306A between two polymer sheets with the following
composition: 45% HPMC, 45% HPC, 10% PEG.
[0099] SLS incorporated in film Accudep.TM. Core: Sealed a 1 mg
deposition of CCN90306A between two polymer sheets with the
following composition: 36% HPMC, 36% HPC, 8% PEG, 20% SLS
(equivalent of about 5 mg SLS incorporated in each Accudep.TM.
Core).
[0100] Polysorbate 80 incorporated in film Accudep.TM. Core: Sealed
a 1 mg deposition of CCN90306A between two polymer sheets with the
following composition: 36% HPMC, 36% HPC, 8% PEG, 20% Polysorbate
80 (equivalent of about 5 mg Polysorbate 80 incorporated in each
Accudep.TM. Core).
[0101] Dissolution profiles for the Accudep.TM. Cores listed above
were generated under the following conditions: 75 rpm, paddles,
distilled water.
[0102] FIG. 7 shows the average dissolution profiles for all the
CCN90306A dissolution runs (n=3). As seen in FIG. 7, the addition
of SLS and Polysorbate in the polymer film led to faster
dissolution at 20- and 30-minute sample points.
Example 3
[0103] Glipizide, CCN90906A, was used to test the effect SLS and
Polysorbate 80 have on dissolution of an Accudep.TM. Core.
Accudep.TM. Cores were made as follows:
[0104] SLS incorporated in film Accudep.TM. Core: Sealed a 1 mg
deposition of CCN90906A between two polymer sheets with the
following composition: 36% HPMC, 36% HPC, 8% PEG, 20% SLS
(equivalent of about 5 mg SLS incorporated in each Accudep.TM.
Core).
[0105] Polysorbate 80 incorporated in film Accudep.TM. Core: Sealed
a 1 mg deposition of CCN90906A between two polymer sheets with the
following composition: 36% HPMC, 36% HPC, 8% PEG, 20% Polysorbate
80 (equivalent of about 5 mg Polysorbate 80 incorporated in each
Accudep.TM. Core).
[0106] Dissolution profiles for the Accudep.TM. Cores listed above
were generated under the following conditions: 50 rpm, paddles,
simulated intestinal fluid.
[0107] FIG. 8 shows the average dissolution profiles for all the
CCN90906A dissolution runs (n=6). As seen in FIG. 8, the addition
of SLS and Polysorbate in the polymer film led to faster
dissolution, especially during the first 60 minutes.
[0108] Although the present invention has been described with
particular reference to certain preferred embodiments thereof,
variations and modifications of the present invention can be
effected within the spirit and scope of the following claims.
* * * * *