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| United States Patent |
6,139,874
|
|
Pather
, et al.
|
October 31, 2000
|
Effervescent drug delivery system for oral administration
Abstract
The pharmaceutical compositions of the present invention comprise orally
administerable dosage forms that use effervescence as a penetration
enhancer for drugs known, or suspected, of having poor bioavailability.
Effervescence can occur in the stomach, once the tablet or other dosage
form is ingested. In addition to effervescence in the stomach, or as
alternative technique, by the use of appropriate coatings and other
techniques, the effervescence can occur in other parts of the
gastrointestinal tract, including, but not limited to, the esophagus,
duodenum, and colon. The site of effervescence and drug release is chosen
to correspond with the segment of the gastrointestinal tract displaying
maximal absorption of the formulated drug, or to gain some other
therapeutic advantage.
| Inventors:
|
Pather; S. Indiran (Plymouth, MN);
Robinson; Joseph R. (Madison, WI);
Eichman; Jonathan D. (Ann Arbor, MI);
Khankari; Rajendra K. (Maple Grove, MN);
Hontz; John (Plymouth, MN);
Gupte; Sangeeta V. (Maple Grove, MN)
|
| Assignee:
|
Cima Labs Inc. (Minneapolis, MN)
|
| Appl. No.:
|
302105 |
| Filed:
|
April 29, 1999 |
| Intern'l Class: |
A61K 009/24; A61K 009/46 |
| Field of Search: |
424/466,465,464,451,489,472,452
|
References Cited
U.S. Patent Documents
| 3961041 | Jun., 1976 | Nishimura et al. | 424/35.
|
| 4289751 | Sep., 1981 | Windheuser | 424/35.
|
| 4503031 | Mar., 1985 | Glassman | 424/15.
|
| 5178878 | Jan., 1993 | Wehling et al. | 424/466.
|
Other References
K. Sashara et al., Dosage Form Design for Improvement of Bioavailibility of
Levodopa IV: Possible Causes of Low Bioavailability of Oral Levodopa in
Dogs, J. Pharm. Sci., (7)70:730-733 (1981).
K. Sashara et al., Dosage Form Design For Improvement of Bioavailability of
Levodopa III: Influence of Dose on Pharmacokinetic Behavior of Levodopa in
Dogs and Parkinsonian Patients, J. Pharm. Sci., (12)69:1374-1378 (1980).
K. Sashara et al., Dosage Form Designe for Improvement of Bioavailability
of Levodopa II: Bioavailability of Marketed Levodopa Preparations in Dogs
and Parkinsonian Patients, J. Pharm. Sci., (3)69 261-265 (1980).
K. Sasahara et al., Dosage form Design for Improvement of Bioavailability
of Levodopa V: Absorption and Metabolism of Levodopa in Intestinal
Segments of Dogs, J. Pharm. Sci., (10)70 1157-1160 (1981).
K. Nishimura et al. Dosage Form Design for Improvement of Bioavailability
for Levodope VI: Formulation of Effervescent Enteric-Coated Tablets, J.
Pharm. Sci., (7)73 942-946 (1984).
|
Primary Examiner: Spear; James M.
Attorney, Agent or Firm: Lerner, David, Littenberg, Krumholtz & Mentlik, LLP
Parent Case Text
The present application claims benefit of U.S. Provisional Patent
application Ser. No. 60/083,391, filed Apr. 29, 1998, the disclosure of
which is hereby incorporated by reference.
Claims
We claim:
1. A dosage form for delivery of a therapeutically effective amount of a
drug to a target area in the gastrointestinal tract of a mammal;
comprising:
(a) a therapeutically effective amount of a drug;
(b) at least one effervescent penetration enhancer; wherein said at least
one effervescent penetration enhancer is present in an amount sufficient
to increase the penetration of said drug across said target area of said
gastrointestinal tract to permit delivery of a therapeutically effective
amount of said drug;
(c) a pH adjusting substance; and
(d) an enteric coating maintained over said drug, said at least one
effervescent penetration enhancer and said pH adjusting substance; wherein
said enteric coating prevents the release of said drug, said at least one
effervescent penetration enhancer and said pH adjusting substance until a
time at which said dosage form reaches said target area in said
gastrointestinal tract.
2. The dosage form of claim 1, wherein said amount of said at least one
effervescent penetration enhancer is equal to about two times the amount
of said drug.
3. The dosage form of claim 1, wherein said amount of said at least one
effervescent penetration enhancer is equal to about three times the amount
of said drug.
4. A tablet for delivery of a therapeutically effective amount of a drug to
a target area in the gastrointestinal tract of a mammal; comprising:
(a) a therapeutically effective amount of a drug;
(b) at least one effervescent penetration enhancer; wherein said at least
one effervescent penetration enhancer is present in an amount sufficient
to increase the penetration of said drug across said target area of said
gastrointestinal tract to permit delivery of a therapeutically effective
amount of said drug;
(c) an enteric coating maintained over said drug; and said at least one
effervescent penetration enhancer; wherein said enteric coating prevents
the release of said drug and said at least one effervescent penetration
enhancer until a time at which said tablet reaches said target area in
said gastrointestinal tract;
said tablet containing a biconcave zone central to two outer zones; wherein
said drug and said effervescent penetration enhancer are located in said
biconcave zone.
5. The dosage form of any one of claims 1-3, further comprising a
bioadhesive, wherein said bioadhesive increases contact time between said
drug and a mucosa layer of said target area.
6. The dosage form of claim 5, wherein said bioadhesive is contained in a
portion of said dosage form external to said drug.
7. The dosage form of any one of claims 1-3, further comprising at least
one noneffervescent penetration enhancer.
8. The dosage form of any one of claims 1-3 further comprising at least one
disintegration agent, wherein said disintegration agent causes the rapid
dispersion of said drug to said target area of said gastrointestinal
tract.
9. The dosage form of any of claims 1-3, wherein said enteric coating
comprises a material that reacts with an enzyme present in said target
area of said gastrointestinal tract to release said drug, said
effervescent penetration enhancer and said pH adjusting substance.
10. The dosage form of any one of claims 1-3, wherein said dosage form is a
tablet.
11. The dosage form of any one of claims 1-3, wherein said dosage form is a
capsule.
12. The dosage form of any one of claims 1-3, wherein said dosage form is
in the form of granules.
13. The dosage form of any one of claims 1-3, wherein said dosage from is
in the form of pellets.
14. The dosage form of claim 10, wherein said tablet contains a biconcave
zone central to two outer zones; wherein said drug, said effervescent
penetration enhancer and said pH adjusting substance are located in said
biconcave zone.
15. The dosage form of claim 14, wherein a bioadhesive is contained in said
two outer zones.
16. The dosage form of claim 1, wherein said effervescent penetration
enhancer comprises a pharmaceutically acceptable effervescent couple; said
effervescent couple comprising an acid or equivalent thereof and a base or
equivalent thereof.
17. The dosage form of claim 16 wherein said base is sodium bicarbonate.
18. The dosage form of claim 16 wherein said base or equivalent thereof is
present in an amount equal to about two times the amount of said drug; and
said acid is present in an amount approximately equimolar to said base.
19. The dosage form of claim 16 wherein said base or equivalent thereof is
present in an amount equal to about three times the amount of said drug;
and said acid is present in an amount approximately equimolar to said
base.
20. The dosage form of claim 1 wherein said drug is a drug that displays
poor bioavailability in said gastrointestinal tract.
21. A dosage form for delivery of a therapeutically effective amount of a
drug to a target area in the gastrointestinal tract of a mammal;
comprising:
(a) a therapeutically effective amount of a drug;
(b) at least one effervescent penetration enhancer; wherein said at least
one effervescent penetration enhancer is present in an amount sufficient
to increase the penetration of said drug across said target area of said
gastrointestinal tract to permit delivery of a therapeutically effective
amount of said drug;
(c) at least one noneffervescent penetration enhancer; and
(d) an enteric coating maintained over said drug, said at least one
effervescent penetration enhancer and said at least one noneffervescent
penetration enhancer; wherein said enteric coating prevents the release of
said drug, said at least one effervescent penetration enhancer and said at
least one noneffervescent penetration enhancer until a time at which said
dosage form reaches said target area in said gastrointestinal tract.
22. The dosage form of claim 21, wherein said amount of said at least one
effervescent penetration enhancer is equal to about-two times the amount
of said drug.
23. The dosage form of claim 21, wherein said amount of said at least one
effervescent penetration enhancer is equal to about three times the amount
of said drug.
24. The dosage form of any one of claims 21-23, further comprising a pH
adjusting substance.
25. The dosage form of any one of claims 21-23, further comprising a
bioadhesive, wherein said bioadhesive increases contact time between said
drug and a mucosa layer of said target area.
26. A dosage form for delivery of a therapeutically effective amount of a
drug to a target area in the gastrointestinal tract of a mammal;
comprising:
(a) a therapeutically effective amount of a drug;
(b) at least one effervescent penetration enhancer; wherein said at least
one effervescent penetration enhancer is present in an amount sufficient
to increase the penetration of said drug across said target area of said
gastrointestinal tract to permit delivery of a therapeutically effective
amount of said drug;
(c) a bioadhesive; wherein said bioadhesive increases contact time between
said drug and a mucosa layer of said target area; and
(d) an enteric coating maintained over said drug, said at least one
effervescent penetration enhancer and said bioadhesive; wherein said
enteric coating prevents the release of said drug and said at least one
effervescent penetration enhancer and the exposure of said bioadhesive
until a time at which said dosage form reaches said target area in said
gastrointestinal tract.
27. The dosage form of claim 26, wherein said amount of said at least one
effervescent penetration enhancer is equal to about two times the amount
of said drug.
28. The dosage form of claim 26, wherein said amount of said at least one
effervescent penetration enhancer is equal to about three times the amount
of said drug.
29. The dosage form of any one of claims 26-28, further comprising a pH
adjusting substance.
30. The dosage form of claim 26, wherein said bioadhesive is contained in a
portion of said dosage form external to said drug.
31. The dosage form of any one of claims 26-28, further comprising at least
one noneffervescent penetration enhancer.
32. The dosage form of any one of claims 26-28, further comprising at least
one disintegration agent, wherein said disintegration agent causes the
rapid dispersion of said drug to said target area of said gastrointestinal
tract.
33. The dosage form of any one of claims 26-28, wherein said enteric
coating comprises a material that reacts with an enzyme present in said
target area of the gastrointestinal tract to release said drug and said
effervescent penetration enhancer.
34. The dosage form of any one of claims 26-28, wherein said dosage form is
a tablet.
35. The dosage form of any one of claims 26-28, wherein said dosage form is
a capsule.
36. The dosage form of any one of claims 26-28, wherein said dosage form is
in the form of granules.
37. The dosage form of any one of claims 26-28, wherein said dosage form is
in the form of pellets.
38. The dosage form of claim 34, wherein said tablet contains a biconcave
zone central to two outer zones; wherein said drug and said effervescent
penetration enhancer are located in said biconcave zone.
39. The dosage form of claim 38, wherein said bioadhesive is contained in
said two outer zones.
40. The dosage form of claim 26, wherein said effervescent penetration
enhancer comprises a pharmaceutically acceptable effervescent couple; said
effervescent couple comprising an acid or equivalent thereof and a base or
equivalent thereof.
41. The dosage form of claim 40, wherein said base is sodium bicarbonate.
42. The dosage form of claim 40, wherein said base or equivalent thereof is
present in an amount equal to about two times the amount of said drug; and
said acid is present in an amount approximately equimolar to said base.
43. The dosage form of claim 40, wherein said base or equivalent thereof is
present in an amount equal to about three times the amount of said drug;
and said acid is present in an amount approximately equimolar to said
base.
44. The dosage form of claim 40, wherein said drug is a drug that displays
poor bioavailability in said gastrointestinal tract.
45. The dosage form of claim 25, wherein said bioadhesive is contained in a
portion of said dosage form external to said drug.
46. The dosage form of any one of claims 21-23, further comprising at least
one disintegration agent, wherein said disintegration agent causes the
rapid dispersion of said drug to said target area of said gastrointestinal
tract.
47. The dosage form of any one of claims 21-23, wherein said enteric
coating comprises a material that reacts with an enzyme present in said
target area of the gastrointestinal tract to release said drug, said
effervescent penetration enhancer, and said noneffervescent penetration
enhancer.
48. The dosage form of any one of claims 21-23, wherein said dosage form is
a tablet.
49. The dosage form of any one of claims 21-23, wherein said dosage form is
a capsule.
50. The dosage form of any one of claims 21-23, wherein said dosage form is
in the form of granules.
51. The dosage form of any one of claims 21-23, wherein said dosage form is
in the form of pellets.
52. The dosage form of claim 48, wherein said tablet contains a biconcave
zone central to two outer zones; wherein said drug, said effervescent
penetration enhancer and said noneffervescent penetration enhancer are
located in said biconcave zone.
53. The dosage form of claim 52, wherein said two outer zones contain a
bioadhesive.
54. The dosage form of claim 21, wherein said effervescent penetration
enhancer comprises a pharmaceutically acceptable effervescent couple; said
effervescent couple comprising an acid or equivalent thereof and a base or
equivalent thereof.
55. The dosage form of claim 54, wherein said base is sodium bicarbonate.
56. The dosage form of claim 54, wherein said base or equivalent thereof is
present in an amount equal to about two times the amount of said drug; and
said acid is present in an amount approximately equimolar to said base.
57. The dosage form of claim 54, wherein said base or equivalent thereof is
present in an amount equal to about three times the amount of said drug;
and said acid is present in an amount approximately equimolar to said
base.
58. The dosage form of claim 21, wherein said drug is a drug that displays
poor bioavailability in said gastrointestinal tract.
59. The tablet of claim 52, wherein said two outer zones contain a
bioadhesive.
Description
BACKGROUND OF THE INVENTION
Many orally-administered drugs display poor bioavailability when
administered in conventional dosage forms, i.e., the rate and extent to
which the drugs are absorbed is less than desirable. With several drugs,
absorption may be as little as 30% or less of the orally administered
dose. To compensate for this effect, a very large dose is often
administered so that absorption of the therapeutically required quantity
of the drug can occur. This technique may prove costly with expensive
drugs; and the nonabsorbed drug may also have undesirable side effects
within the gastrointestinal tract. In addition, poorly absorbed drugs
often display large inter- and intrasubject variability in
bioavailability. See Aungst, B. J., J. Pharm. Sci., 82:979-987, 1993.
Specific examples (with the average bioavailability given in parentheses)
include methyldopa (25%) with a range of 8% to 62%. See Kwan, K. C., Folz,
E. L., Breault, G. O., Baer, J. E., Totaro, J. A., J. Pharmacol. Exp.
Ther., 198:264-277, 1976; and nalbuphine (approximately 17%) with a range
of 6% to 40%. See Lo. M. -W, Schary, W. L., Whitney, C. C., Jr., J. Clin.
Pharmacol., 27:866-873, 1987. Such variation in the amount of drug
absorbed does not allow for good control of the disease condition.
To improve the bioavailability of poorly absorbed drugs, penetration
enhancers have also been employed. However, many of the penetration
enhancers referred to in the current literature damage the absorbing
tissues and thus are not a practical solution to the problem of poor
bioavailability. In fact, it has been suggested that the damage to the
mucosa caused by these agents may be the factor responsible for the
improved absorption. See LeCluyse, E. L. and Sutton, S. C., Advanced Drug
Delivery Reviews, 23:163-183, 1997.
Other techniques which have been employed to improve bioavailability
include using enteric coated tablets having effervescence to rapidly
dissolve or disperse the dosage form in the stomach. See U.S. Pat. Nos.
4,503,031; 4,289,751; and 3,961,041.
SUMMARY OF THE INVENTION
The pharmaceutical compositions of the present invention comprise orally
administerable dosage forms that use effervescence as a penetration
enhancer for drugs known, or suspected, of having poor bioavailability.
Effervescence can occur in the stomach, once the tablet or other dosage
form is ingested. In addition to effervescence in the stomach, or as
alternative technique, by the use of appropriate coatings and other
techniques, the effervescence can occur in other parts of the
gastrointestinal tract, including, but not limited to, the esophagus,
duodenum, intestinal and colon. The site of effervescence and drug release
is chosen to correspond with the segment of the gastrointestinal tract
displaying maximal absorption of the formulated drug, or to gain some
other therapeutic advantage. Desirably, such site is not in the mouth of
the subject.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1. is an enlarged top plan view of a tablet which has a bioconcaved
shaped.
FIG. 2. is an enlarged side view of an enteric coated multilayered tablet.
FIG. 3. is an enlarged top view of an enteric coated multilayered tablet,
which depicts the effervescent external to the mucous adhesive layer.
FIG. 4. is an enlarged top view of an enteric coated multilayered pellet,
which depicts the effervescent external to the mucous adhesive layer.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The pharmaceutical compositions of the present invention comprise orally
administerable medicaments in combination with an effervescent as a
penetration enhancer for influencing absorption of a drug in the
gastrointestinal tract. Effervescence leads to an increase in the rate
and/or the extent of absorption of the drugs that are known or suspected
of having poor bioavailability. It is believed that such increase can rise
from one or all of the following mechanisms:
1. reducing the thickness and/or the viscosity of the mucus layer which is
present adjacent to the gastrointestinal mucosa;
2. alteration of the tight junctions between cells, thus promoting
absorption through the paracellular route;
3. inducing a change in the cell membrane structure, thus promoting
transcellular absorption;
4. increasing the hydrophobic environment within the cellular membrane.
The present dosage forms include an amount of effervescent agent effective
to aid in penetration of the drug in the gastrointestinal tract. The
amount of effervescent employed must not merely permit rapid dispersion of
the medicament in the gastrointestinal tract, but must aid in penetration
of the drug across the gastrointestinal mucosa. The formulations of the
present invention may be distinguished from other effervescent formulation
that are enteric coated on the basis of the amount of effervescent
material that they contain. Prior formulations contain approximately half
to a quarter as much bicarbonate as drug on a weight basis (together with
a proportionate amount of acid). In these cases, the small amount of
effervescent couple serves only to rapidly disintegrate the tablet.
The dosage forms of the present invention should preferably contain at
least twice as much sodium bicarbonate (or an equivalent amount of other
base) as drug (on a weight basis) together with the proportionate amount
of an appropriate acid for generating the effervescent reaction. More
preferably the present dosage forms should contain at least three times as
much sodium bicarbonate as drug (on a weight basis) together with the
proportionate amount of an appropriate acid. These high concentrations of
effervescent couple are needed to generate effervescence in sufficient
amounts to promote permeability and absorption of the drug.
Preferably, the effervescent is provided in an amount of between about 5%
and about 95% by weight, based on the weight of the finished tablet, and
more preferably in an amount of between about 30 to about 60%. However,
the amount of effervescent agent must be optimized for each specific drug.
The term "effervescent penetration enhancer" includes compounds which
evolve gas. The preferred effervescent penetration enhancers evolve gas by
means of a chemical reaction which takes place upon exposure of the
effervescent penetration enhancer to water and other fluids. Such
water-activated materials must be kept in a generally anhydrous state and
with little or no absorbed moisture or in a stable hydrated form, since
exposure to water will prematurely disintegrate the tablet. The acid
sources may be any which are safe for human consumption and may generally
include food acids, acid and hydrite antacids such as, for example,
citric, tartaric, amalic, fumeric, adipic, and succinics. Carbonate
sources include dry solid carbonate and bicarbonate salt such as,
preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate
and potassium carbonate, magnesium carbonate and the like.
The effervescent penetration enhancers of the present invention is not
limited to those which are based upon a reaction which forms carbon
dioxide. Reactants which evolve oxygen or other gases and which are safe
for human consumption are also considered within the scope of the present
invention.
The present dosage forms may also include in amounts additional to that
required for effervescence a pH adjusting substance. For drugs that are
weekly acidic or weakly basic, the pH of the aqueous environment can
influence the relative concentrations of the ionized and the unionized
forms of the drug present in solution, according to the
Henderson-Hasselbach equation. Th pH of solutions in which an effervescent
couple with equimolar amounts of base and acid has dissolved is slightly
acidic due to the evolution of CO.sub.2. While it is impractical and may
not be desirable to change the pH of the contents of the small intestine,
it is, nevertheless, possible to alter the pH of the local environment
(intestinal contents in immediate contact with the tablet and any drug
that may have dissolved from it). This is achieved by incorporating in the
tablet certain pH adjusting substances. Thus, the relative proportions of
the ionized and unionized forms of the drug may be controlled.
In this way the system can be optimized for each specific drug under
consideration: if the drug is known, or suspected, to be absorbed through
the cell membrane (transcellular absorption), it would be most appropriate
to alter the pH of the local environment to a level that favors the
unionized form of the drug. Conversely, if the ionized form is more
readily dissolved the local environment should favor ionization. Thus, for
fentanyl, as a nonlimiting example, the pH is adjusted to neutral (or
slightly higher) since the pKa is 7.3. At this pH, the aqueous solubility
of this poorly water-soluble drug is not compromised unduly, yet allowing
a sufficient concentration of the drug to be present in the unionized
form. This facilitates the permeation enhancement brought about by
effervescence. In the case of prochlorperazine (pKa=8.1), a slightly
higher pH is required.
Suitable pH adjusting substance for use in the present invention include
any weak acid or weak base (in amounts additional to that required for
effervescence) or, preferably, any buffer system that is not harmful to
the gastrointestinal mucosa. These include, but are not limited to, any of
the acids or bases previously mentioned as the effervescent components,
sodium carbonate, potassium carbonate, potassium carbonate, disodium
hydrogen phosphate, sodium dihydrogen phosphate, and the equivalent
potassium salts.
The active agents suitable for use in the present invention preferably
includes any drug that displays poor bioavailability, slow absorption or
long t.sub.max. These active ingredients include small molecule drugs,
nutritional supplements (such as vitamins and minerals), proteins and
peptides and other substances of biological origin. Examples of such drugs
include, but are not limited to, the following:
______________________________________
Drug Bioavailability (%)
______________________________________
Acyclovir 15-30
Auranofin 15-25
Bretylium 23 .+-. 9
Cyclosporine 23 .+-. 7
Cytarabine 20
Doxepin 27 .+-. 10
Doxorubicin 5
Hydralazine 16-35
Ketamine 20 .+-. 7
Labetalol 18 .+-. 5
Mercaptopurine
12 .+-. 7
Methyldopa 25 .+-. 16
Nalbuphine 25 .+-. 16
Naloxone 2
Pentoxifylline
19 .+-. 13
Pyridostigmine
14 .+-. 3
Terbutaline 14 .+-. 2
Verapamil 22 .+-. 8
Riboflavin 11
Atenolol 50
______________________________________
Pharmaceutical ingredients suitable for use in the present dosage forms may
include, without limitation, analgesics, anti-inflammatories,
antipyretics, antibiotics, antimicrobials, laxatives, anorexics,
antihistamines, antiasthmatics, antidiuretics, antiflatuents, antimigraine
agents, antispasmodics, sedatives, antihyperactives, antihypertensives,
tranquilizers, decongestants, beta blockers; peptides, proteins,
oligonucleotides and other substances of biological origin, and
combinations thereof. Also encompassed by the terms "active
ingredient(s)", "pharmaceutical ingredient(s)" and "active agents" are the
drugs and pharmaceutically active ingredients described in Mantelle, U.S.
Pat. No. 5,234,957, in columns 18 through 21. That text of Mantelle is
hereby incorporated by reference. Alternatively or additionally, the
active ingredient can include drugs and other pharmaceutical ingredients,
vitamins, minerals and dietary supplements as the same are defined in U.S.
Pat. No. 5,178,878, the disclosure of which is also incorporated by
reference herein.
The dosage forms preferably contain materials that aid in releasing the
drug in a specific section of the gastrointestinal tract, thus promoting
site-specific delivery. There are various mechanisms by which such
materials promote site-specific delivery and this invention is not limited
to any one mechanism. For example, the material may be metabolized by
enzymes present in a specific part of the gastrointestinal tract, thus
releasing the drug in that section.
The materials used to promote site-specific absorption may preferably be
included as coatings and/or as matrix materials. If a coating is used, it
may be applied to the entire dosage form or to the individual particles of
which it consists. Coating materials may be used to prevent the release of
the active agent before the dosage form reaches the site of more efficient
absorption.
The coating can also be used in conjunction with an effervescence to cause
the effervescence to occur at specific areas of the gastrointestinal
tract. Nonlimiting examples or coatings used in the present invention
include: cellulose derivatives including cellulose acetate phthalate
(CAP); shellac and certain materials sold under the trademark Eudragit.TM.
(various grades may be used in specific combinations). Hydroxypropylmethyl
cellulose phthallate in a grade that dissolves at pH 5 is the preferred
coating material.
Precoating materials may also be used in the present invention. Nonlimiting
examples include cellulose derivatives such as methylcellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose or combinations and
certain materials sold under the trademark Eudragit.TM. (various grades
which may be combined). Hydroxypropylmethyl cellulose phthallate in a
grade that dissolves at pH 5 is the preferred coating material.
Other materials may be used to aid in site specific delivery, and include,
for example, sugars, polysaccharides, starches, polymers, etc. These
compounds may be included as coatings or as matrix materials and aid in
releasing the drug in specific sections of the gastrointestinal tract,
thus promoting site-specific delivery.
Other ingredients or techniques may preferably be used with the present
dosage forms to enhance the absorption of the pharmaceutical ingredient,
to improve the disintegration profile, and/or to improve the organoleptic
properties of the material and the like. These include, but are not
limited to, the use of additional chemical penetration enhancers;
absorption of the drug onto fine particles to promote absorption by
specialized cells within the gastrointestinal tract (such as the M cells
of Peyer's patches); ion pairing or complexation; and the use of lipid
and/or surfactant drug carriers. The selected enhancement technique is
preferably related to the route of drug absorption, i.e., paracellular or
transcellular.
A bioadhesive polymer may preferably be included in the drug delivery
device to increase the contact time between the dosage form and the mucosa
of the most efficiently absorbing section of the gastrointestinal tract.
See Jonathan D. Eichman, "Mechanastic Studies on Effervescent-Induced
Permeability Enhancement," University of Wisconsin-Madison (1997), hereby
incorporated by reference. Nonlimiting examples of known bioadhesives used
in the present invention include: carbopol (various grades), sodium
carboxy methylcellulose, methylcellulose, polycarbophil (Noveon AA-1),
hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate,
and sodium hyaluronate.
Disintegration agents may also be employed to aid in dispersion of the drug
in the gastrointestinal tract. Disintegration agents include any
pharmaceutically acceptable effervescent agent. In addition to the
effervescence-producing disintegration agents, a dosage form according to
the present invention may include suitable noneffervescent disintegration
agents. Nonlimiting examples of disintegration agents include:
microcrystalline cellulose, croscarmelose sodium, crospovidone, starches
and modified starches.
Apart from the effervescent material within the tablet, some additional
effervescent components or, alternatively, only sodium bicarbonate (or
other alkaline substance) may be present in the coating around the dosage
form. The purpose of the latter effervescent/alkaline material is to react
within the stomach contents and promote faster stomach emptying.
The drug delivery device may be in the form of a tablet, granules, pellets
or other multiparticulates, capsules that can contain the drug in the form
of minitablets, beads, or a powder, or any other suitable dosage form.
If tablets are used, they may be matrix tablets; layered tablets in which
the various components are separated in different layers to optimize their
benefits; or other specialized forms of tablets, including nonconventional
shapes and geometric arrangements. One example of a nonconventional shape
is a flat-faced tablet with a biconcave central zone, as depicted in FIG.
1. The outer, thicker part of the tablet may contain the mucoadhesive
material while the inner, thinner segment may contain the drug and
effervescent components. This arrangement allows drug release to a segment
of the gastrointestinal mucosa in close proximity to the point at which
the tablet is attached to the mucosa.
The drug and/or the effervescent material could be present in a sustained
release matrix. The whole tablet may consist of this matrix or the matrix
may be confined to one, or more, layers of a multilayered tablet. FIG. 2
depicts a multilayered tablet with a central layer containing the drug and
optional effervescent material; and two mucoadhesive layers. The tablet
would adhere to the mucosa irrespective of its spatial orientation within
the intestine.
FIGS. 3 and 4 depict the effervescent layer external to the mucoadhesive
layer of each dosage form. FIG. 3 depicts a multilayered tablet in which a
central core is completely surrounded by each subsequent layer. Such a
tablet may be prepared by a compression coating technique. A similar
physical arrangement of layers can also be achieved in a spheroid or
pellet which may be prepared by extrusion and spheronization, layering,
coating or any combination of these techniques. (See FIG. 4.) The
effervescence will cause a thinning of the mucus layer from the
gastrointestinal segment, thus facilitating adhesive of the dosage form to
the cellular surface rather than to the mucus layer. This arrangement
promotes better absorption of the drug.
Tablets can be manufactured by wet granulation, dry granulation, direct
compression or any other tablet manufacturing technique. The tablet may be
a layered tablet consisting of a layer of the active ingredients set forth
above in layers of diverse compositions. In accordance with the present
invention, the tablet size is preferably up to about 3/4". In accordance
with the present invention, the multiparticulate size is preferably up to
about 3 mm. In accordance with the present invention, the tablet hardness
is preferably between about 5N and 100N.
Excipient fillers can be used in connection with the present invention to
facilitate tableting. Nonlimiting examples of fillers include: mannitol,
dextrose, lactose, sucrose, and calcium carbonate.
Pellets or other multiparticulates may be manufactured by granulation,
layering techniques, extrusion and spheronization or other pellet
manufacturing methods. The multiparticulates are then coated with an
enteric coating material as described for tablets. The coating is
preferably done in a fluid bed coater. The preferred, but nonlimiting,
coating material is hydroxypropylmethyl cellulose in a grade that
dissolves at pH 5. The multiparticulates are then packed into capsules.
The granules may be made by a wet granulation process or a dry granulation
process. When wet granulation is used, isopropyl alcohol, ethyl alcohol or
other nonaqueous granulating agent is used. Low moisture content grades of
these organic solvents are used.
Dry granulation may be achieved through slugging or chilsonation. Layering
may be done in a fluid bed apparatus or coating pan. Nonaqueous binders
are used to aid the adherence of the added material (drug, effervescent
penetration enhancer and excipients) to the starting material. Nonlimiting
examples of the starting material or cores are nonpareils (sucrose) or
microcrystalline cellulose seeds.
The preferred technique for the manufacture of multiparticulates is
extrusion and spheronization. The beads contain the drug, effervescent
couple (as previously described), a fine particle diluent which also aids
in the formation of the beads (examples are lactose and mannitol) and a
spheronization aid such as microcrystalline cellulose. The preferred grade
of the latter is Avicel RC 591 which contains sodium carboxymethyl
cellulose as an additional ingredient. For this formulation, a nonaqueous
solvent is used. Nonlimiting examples of nonaqueous solvents are
isopropanol and ethanol. Low moisture content grades are used.
The alternate (and preferred) formulation is to manufacture two populations
of beads, one containing the acid component and the other the alkaline
component of the effervescent couple. Each population of beads contains
similar drug concentrations and can be manufactured using water. Care
should be taken to ensure that each population of beads has a similar size
range and a similar density. Equal densities may be achieved by the
incorporation of a nontoxic material of high density to the population of
beads that would, otherwise, have had a lower density. A nonlimiting
example of such a material is barium sulfate. Equivalence of size and
density facilitates the achievement of similar emptying rates of the beads
from the stomach once the dosage forms are consumed by the subject. When
the beads come into contact with the intestinal fluids, the coating
dissolves and the close proximity of the beads to each other allows the
effervescent reaction to occur in situ.
The coating applied to the dosage forms of the present invention must be
performed with precision to avoid pinhole faults since water penetration
through such faults leads to rapid and premature disintegration of the
tablet. Such coating can be performed by one skilled in the art who,
additionally, takes precautions to limit abrasion and chipping of the
partially formed coat during the coating process. A fluid bed coater, pan
coater or other coating apparatus may preferably be used.
The invention will be further described by reference to the following
detailed examples. These examples are provided for the purposes of
illustration only, and are not intended to be limiting unless otherwise
specified.
EXAMPLE 1
Riboflavin
______________________________________
INGREDIENTS mg/TABLET
______________________________________
Riboflavin, USP 5
Silicified Microcrystalline Cellulose
19.7
Sodium Bicarbonate 18.2
Citric Acid, Anhydrous
13
Crospovidone 3
Magnesium Stearate 0.9
Colloidal Silicon Dioxide
0.5
TOTAL 60
______________________________________
The tablets were compressed to a hardness of 50 N using 3/16 inch concave
punches. The tablets had a friability of less than 0.25%. Coating solution
was prepared according to the following formula:
______________________________________
INGREDIENTS WEIGHT (gm)
______________________________________
Hydroxypropylmethyl cellulose phthallate
418.5
Triethylcitrate 31.5
Ethanol 2025.0
Acetone 2025.0
TOTAL 4500.0
______________________________________
Using a fluidized bed coater, the tablets were coated to a 15% weight gain.
Care was taken to fluidize the bed sufficiently so that agglomeration of
the tablets did not occur during coating but excessive movement was
avoided to minimize chipping of the tablets or abrasion of the coating
material.
EXAMPLE 2
Atenolol
______________________________________
INGREDIENTS mg/PER TABLET
______________________________________
Atenolol 7.143
Sodium bicarbonate 15.000
Citric acid 10.714
Silicified microcrystalline cellulose
26.043
Magnesium stearate 0.900
Silicon dioxide 0.200
TOTAL 60.000
______________________________________
The tablets were compressed using 3/16 inch concave punches to a hardness
of 40 N. The tablets were coated with hydroxypropylmethyl cellulose
phthallate solution as described above to a weight gain of 15%. Seven
tablets were packed into a size 0 elongated capsule to form the final
dosage form.
EXAMPLE 3
Atenolol Population 1
______________________________________
INGREDIENTS mg PER CAPSULE
______________________________________
Atenolol 25
Sodium bicarbonate
150
Lactose 37
Avicel RC 591 38
Water Qs
TOTAL 250
______________________________________
The dry powders were blended together. Water was slowly added with mixing
until a wet mass that was plastic (but not tacky) was formed. The wet mass
was passed through an extruder. The extruded material was spheronized for
3 minutes. The beads that were formed were air dried for one hour and then
dried in an oven at 35.degree. C. overnight. The beads were sieved to
remove large particles and fines.
EXAMPLE 4
Atenolol Population 2
______________________________________
INGREDIENTS mg PER CAPSULE
______________________________________
Atenolol 25
Citric acid 107
Lactose 80
Avicel RC 591 38
Water Qs
TOTAL 250
______________________________________
Population 2 was made in a similar fashion to population 1. Each population
of beads was separately coated to a 20% weight gain in a fluidized bed
coater using the previously described coating solution. Two hundred and
fifty milligrams of each population of beads was filled into size 0
elongated capsules and this formed the final dosage form.
Various modifications of the invention described herein will become
apparent to those skilled in the art. Such modifications are intended to
fall within the scope of the appending claims.
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