U.S. patent application number 10/740213 was filed with the patent office on 2004-09-02 for sustained release matrix systems for highly soluble drugs.
This patent application is currently assigned to Penwest Pharmaceuticals Co.. Invention is credited to Baichwal, Anand R., Labudzinski, Steve, Liu, Lirong, McCall, Troy W..
Application Number | 20040170684 10/740213 |
Document ID | / |
Family ID | 22562739 |
Filed Date | 2004-09-02 |
United States Patent
Application |
20040170684 |
Kind Code |
A1 |
Baichwal, Anand R. ; et
al. |
September 2, 2004 |
Sustained release matrix systems for highly soluble drugs
Abstract
Disclosed are sustained release oral solid dosage forms
comprising a therapeutically effective amount of a medicament
having a solubility of more than about 10 g/l; a pH modifying
agent; and a sustained release matrix comprising a gelling agent,
said gelling agent comprising a heteropolysaccharide gum and a
homopolysaccharide gum capable of cross-linking said
heteropolysaccharide gum when exposed to an environmental fluid,
said dosage form providing a sustained release of said medicament
after oral administration to human patients.
Inventors: |
Baichwal, Anand R.;
(Wappingers Falls, NY) ; McCall, Troy W.;
(Germantown, TN) ; Liu, Lirong; (Washington
Township, NJ) ; Labudzinski, Steve; (Poughkeepsie,
NY) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Assignee: |
Penwest Pharmaceuticals Co.
Patterson
NY
|
Family ID: |
22562739 |
Appl. No.: |
10/740213 |
Filed: |
December 18, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10740213 |
Dec 18, 2003 |
|
|
|
09676376 |
Sep 29, 2000 |
|
|
|
60157200 |
Sep 30, 1999 |
|
|
|
Current U.S.
Class: |
424/468 |
Current CPC
Class: |
A61P 9/10 20180101; A61K
9/205 20130101; A61P 9/12 20180101; A61P 13/02 20180101; A61K
9/2077 20130101; A61P 25/04 20180101; A61K 9/2846 20130101; A61K
9/167 20130101; A61P 9/00 20180101; A61P 25/08 20180101; A61K
9/2866 20130101; A61K 9/2009 20130101; A61K 9/2018 20130101; A61K
31/554 20130101; A61K 9/2013 20130101; A61P 9/06 20180101 |
Class at
Publication: |
424/468 |
International
Class: |
A61K 009/22 |
Claims
What is claimed is:
1. A sustained release oral solid dosage form comprising: an
therapeutically effective amount of a medicament having a
solubility of more than about 10 g/l; a pH modifying agent; a
sustained release matrix comprising a gelling agent, said gelling
agent comprising a heteropolysaccharide gum and a
homopolysaccharide gum capable of cross-linking said
heteropolysaccharide gum when exposed to an environmental fluid,
said dosage form providing a sustained release of said medicament
after oral administration to human patients.
2. The sustained release oral solid dosage form of claim 1 which
provides a sustained release of said medicament for at least about
12 hours after oral administration.
3. The sustained release oral solid dosage form of claim 1 which
provides a sustained release of said medicament for at least about
24 hours after oral administration.
4. The sustained release oral solid dosage form of claim 1, wherein
said medicament has a solubility of more than about 100 g/l.
5. The sustained release oral solid dosage form of claim 1, wherein
said medicament has a solubility of more than about 1000 g/l.
6. The sustained release oral solid dosage form of claim 1, further
comprising an inert pharmaceutical diluent.
7. The sustained release oral solid dosage form of claim 6, wherein
said inert diluent is selected from the group consisting of
monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures
thereof.
8. The sustained release oral solid dosage form of claim 6, wherein
the ratio of said inert diluent to said gelling agent is from about
1:3 to about 3:1
9. The sustained release oral solid dosage form of claim 1, wherein
the ratio of said medicament to said gelling agent is from about
1:5 to about 5:1.
10. The sustained release oral solid dosage form of claim 1,
further comprising an ionizable gel strength enhancing agent
capable of crosslinking with said gelling agent and increasing the
gel strength when the dosage form is exposed to an environmental
fluid.
11. The oral solid dosage form of claim 10, wherein said ionizable
gel strength enhancing agent comprises an alkali metal or an
alkaline earth metal sulfate, chloride, borate, bromide, citrate,
acetate, or lactate.
12. The oral solid dosage form of claim 11, wherein said ionizable
gel strength enhancing comprises calcium sulfate.
13. The oral solid dosage form of claim 1, wherein said
heteropolysaccharide gum comprises xanthan gum and said
homopolysaccharide gum comprises locust bean gum.
14. The oral solid dosage form of claim 1, wherein said pH
modifying agent is an organic acid.
15. The sustained release oral solid dosage form of claim 14,
wherein said organic acid is selected from the group consisting of
citric acid, succinic acid, fumaric acid, malic acid, maleic acid,
glutaric acid, lactic acid and combinations thereof.
16. The sustained release oral solid dosage form of claim 15,
wherein said organic acid is fumaric acid.
17. The oral solid dosage form of claim 1, wherein said pH
modifying agent is present in an amount from about 1% to about
10%.
18. The oral solid dosage form of claim 1, further comprising a
surfactant.
19. The oral solid dosage form of claim 18, wherein said surfactant
is selected from the group consisting of anionic surfactants,
cationic surfactants, amphoteric (amphipathic/amphophilic)
surfactants, and non-ionic surfactants.
20. The oral solid dosage form of claim 18, wherein said surfactant
is selected from the group consisting of sodium lauryl sulfate and
a pharmaceutically effective salt of docusate.
21. The oral solid dosage form of claim 1, wherein said sustained
release matrix further comprises a hydrophobic material.
22. The oral solid dosage form of claim 21, wherein said
hydrophobic material is selected from the group consisting of an
alkylcellulose, a copolymer of acrylic and methacrylic acid esters,
waxes, shellac, zein, hydrogenated vegetable oil, and mixtures
thereof, in an amount effective to slow the hydration of said
gelling agent when exposed to an environmental fluid.
23. The oral solid dosage form of claim 21, wherein said
hydrophobic material is ethylcellulose.
24. The oral solid dosage form of claim 5, wherein said sustained
release matrix comprises from about 1 to about 20% by weight of
said hydrophobic material.
25. The oral solid dosage form of claim 1, further comprising from
about 1 to about 10% by weight microcrystalline cellulose.
26. The oral solid dosage form of claim 1, wherein said medicament
is a benzothiazine.
27. The oral solid dosage form of claim 26, wherein said
benzothiazine is diltiazem or a pharmaceutically effective salt
thereof.
28. The oral solid dosage form of claim 27, which provides a
sustained release of said diltiazem for at least about 12 hours
after oral administration to human patients.
29. The oral solid dosage form of claim 28 wherein said diltiazem
is present in an amount from about 60 mg to about 120 mg.
30. The oral solid dosage form of claim 27, which provides a
sustained release of said diltiazem for at least about 24 hours
after oral administration to human patients.
31. The oral solid dosage form of claim 30 wherein said diltiazem
is present in an amount from about 120 mg to about 300 mg.
32. The oral solid dosage form of claim 1, wherein said medicament
is an antispasmodic agent.
33. The oral solid dosage form of claim 32, wherein said
antispasmodic drug is oxybutynin or a pharmaceutically acceptable
salt thereof.
34. The oral solid dosage form of claim 33, wherein said
antispasmodic agent is oxybutynin chloride.
35. The oral solid dosage form of claim 33, which provides a
sustained release of said oxybutynin for at least 12 hours after
oral administration to human patients.
36. The oral solid dosage form of claim 35, wherein said oxybutynin
is present in an amount from about 2.5 mg to about 25 mg.
37. The oral solid dosage form of claim 33, which provides a
sustained release of said oxybutynin for at least about 24 hours
after oral administration to human patients.
38. The oral solid dosage form of claim 37, wherein said oxybutynin
is present in an amount from about 5 mg to about 50 mg.
39. The oral solid dosage form of claim 1 which is a tablet.
40. The oral solid dosage form of claim 1 which is in granular
form.
41. The oral solid dosage form of claim 40, wherein a portion of
said medicament is outside the granulation.
42. The oral solid dosage form of claim 40, wherein a sufficient
amount of said granules to provide an effective dose of said
medicament are disposed in a pharmaceutically acceptable
capsule.
43. The oral solid dosage form of claim 39 wherein at least part of
a surface of said tablet is coated with a hydrophobic material to a
weight gain from about 1 to about 20 percent, by weight.
44. The oral solid dosage form of claim 43, wherein said
hydrophobic material is selected from the group consisting of an
alkylcellulose, a copolymer of acrylic and methacrylic acid, waxes,
shellac, zein, hydrogenated vegetable oils, and mixtures of any of
the foregoing.
45. The sustained release oral dosage form of claim 18 which
provides bimodal absorption profile of said medicament.
46. A sustained release oral solid dosage form comprising: an
effective amount of a calcium channel blocker to provide a
therapeutic effect, said calcium channel blocker having a
solubility greater than 10 g/L; a pH modifying agent; a
pharmaceutically acceptable surfactant a sustained release
excipient comprising a gelling agent, said gelling agent comprising
a heteropolysaccharide gum and a homopolysaccharide gum capable of
cross-linking said heteropolysaccharide gum when exposed to an
environmental fluid, said dosage form providing bimodal absorption
profile of said calcium channel blocker and providing a sustained
release of said calcium channel blocker for at least about 12 hours
after oral administration to human patients.
47. The oral solid dosage form of claim 46, wherein said calcium
channel blocker is a benzothiazine.
48. The oral solid dosage form of claim 46, wherein said
benzothiazine is diltiazem or a pharmaceutically acceptable salt
thereof.
49. The oral solid dosage form of claim 48, wherein said dosage
form provides an initial peak concentration (Cmax #1) of said
diltiazem in about 4 to about 10 hours after oral administration of
the dosage form, followed by a second peak concentration (Cmax #2)
which occurs in about 10 to about 16 hours after oral
administration of the dosage form, said dosage form providing a
therapeutic effect for at least about 24 hours after oral
administration to a human patient.
50. The dosage form of claim 49, wherein said time to first peak
plasma concentration (Tmax #1) of diltiazem occurs in about 6 to
about 8 hours after oral administration of the dosage form to the
patient.
51. The dosage form of claim 49, wherein the maximum plasma
concentration of diltiazem at the first. Tmax (Cmax #1) is from
about 50 to about 100 ng/ml, per administration of a 240 mg dosage
of diltiazem.
52. The dosage form of claim 46, wherein the second peak plasma
concentration (Cmax #2) occurs in about 12 to about 14 hours after
oral administration of the dosage form to the patient (Tmax
#2).
53. The dosage form of claim 52, wherein the maximum plasma
concentration of diltiazem at Cmax #2 is from about 60 to about 90
ng/ml, per 240 mg diltiazem.
54. The dosage form of claim 46, wherein the width of the plasma
concentration curve at 50% of the height of Cmax #1, based on a
trough taken as the Cmin between Cmax #1 and. Cmax #2 is from about
0.5 to about 4.0 hours.
55. The dosage form of claim 46, wherein the width of the plasma
concentration curve at 50% of the height of Cmax #1, based on a
trough taken as the Cmin between Cmax #1 and Cmax #2 is from about
1 to about 3 hours.
56. The dosage form of claim 46, wherein the width of the plasma
concentration curve at 50% of the height of Cmax #2, based on a the
trough taken as the Cmin between Cmax #1 and Cmax #2 is from about
0.5 to about 8 hours.
57. The dosage form of claim 46, wherein the width of the plasma
concentration curve at 50% of the height of Cmax #2, based on a the
trough taken as the Cmin between Cmax #1 and Cmax #2 is from about
2 to about 6 hours.
58. The dosage form of claim 49, wherein the ratio of Cmax #1 to
Cmax #2 is from about 0.5:1 to about 1.5:1.
59. The dosage form of claim 58, wherein the ratio of Cmax #1 to
Cmax #2 is from about 0.7:1 to about 1.2:1.
60. A method of treating a human patient suffering from a disease
state selected from the group consisting of hypertension, angina,
aneurysms, arythmias, and headache comprising administering to said
patient a dosage form of claim 46.
61. A sustained release oral solid dosage form comprising: an
effective amount of oxybutynin or a pharmaceutically acceptable
salt thereof to provide a therapeutic effect, a pH modifying agent;
a sustained release excipient comprising a gelling agent, said
gelling agent comprises a heteropolysaccharide gum and a
homopolysaccharide gum capable of cross-linking said
heteropolysaccharide gum, said dosage form providing a therapeutic
effect for at least about 24 hours after administration to human
patients.
62. The sustained release oral solid dosage form of claim 61 which
provides a time to peak plasma concentration (Tmax) in about 5 to
about 15 hours
63. The sustained release oral solid dosage form of claim 62 which
provides a time to peak plasma concentration (Tmax) in about 8 to
about 12 hours.
64. A method of treating a human patient suffering from
incontinence comprising administering to said patient a dosage form
of claim 61.
Description
[0001] This application claims the benefit of provisional
application Serial No. 60/157,200 filed Sep. 30, 1999, the
disclosure of which is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The advantages of controlled release products are well known
in the pharmaceutical field and include the ability to maintain a
desired blood level of a medicament over a comparatively longer
period of time while increasing patient compliance by reducing the
number of administrations necessary to achieve the same. These
advantages have been attained by a wide variety of methods. For
example, different hydrogels have been described for use in
controlled release medicines, some of which are synthetic, but most
of which are semi-synthetic or of natural origin. A few contain
both synthetic and non-synthetic material. However, some of the
systems require special process and production equipment, and in
addition some of these systems are susceptible to variable drug
release.
[0003] Oral controlled release delivery systems should ideally be
adaptable so that release rates and profiles can be matched to
physiological and chronotherapeutic requirements.
[0004] For the most part, the release rate of oral delivery systems
have been classified according to the mechanism of release, such as
zero order, first order, second order, pseudo-first order, and the
like, although many pharmaceutical compounds release medicament via
other, complicated mechanisms.
[0005] First order mechanisms refer to situations where the
reaction rate is dependent on the concentration of the reacting
substance (and therefore is dependent on the first power of the
reactant). In such mechanisms, the substance decomposes directly
into one or more products.
[0006] Second order mechanisms occur when the experimentally
determined rate of reaction is proportional to the concentration of
each of two reactants, or to the second power of the concentration
of one reactant.
[0007] Pseudo first order reactions are generally defined as second
order reactions which behave as though they are governed by a first
order mechanism, and occur, for example, when the amount of one
reacting material is manipulated by being present in great excess
or being maintained at a constant concentration as compared to the
other substance. In such circumstances, the reaction rate is
determined by the manipulated substance.
[0008] Zero order mechanisms refer to situations where the reaction
rate is independent of the concentration of the reacting substance
(and therefore is dependent on the zero power of the reactant), the
limiting factor being something other than the concentration of the
reacting substance (e.g., the medicament). The limiting factor in a
zero order mechanism may be, for example, the solubility of the
reacting substance or the light intensity in photochemical
reactions.
[0009] As previously mentioned, however, many chemical reactions
are not simple reactions of zero-, first-, or second-order, and the
like, and instead comprise a combination of two or more
reactions.
[0010] Moreover, other factors may influence the reaction rate,
including temperature, pH, food effect variability, ions and ionic
strength dependency, viscosity dependency, corrosion/erosion
variability, content uniformity problems, flow and weight
uniformity problems, carrying capacity and mechanical strength
problems, hydrolysis, photochemical decomposition, interaction
between components (such as interactions between the drug and other
ingredients in the formulation, such as buffers, preservatives, and
the like), the concentration of solvents of low dielectric constant
(when the reaction involves oppositely charged ions), etc.
[0011] While many controlled and sustained release formulations are
already known, certain soluble to highly soluble drugs present
formulation difficulties when included in such formulations.
Sustained release formulations with soluble drugs are susceptible
to "dose dumping". This occurrence is where the release of the
active ingredient is delayed, but when release is initiated, the
rate is extremely high. This elevated release rate is associated
with blood plasma fluctuations which can possibly result in
decreased therapeutic effect or increased toxicity. These are the
same problems which sustained release formulations are supposed to
solve.
[0012] Further, it is often not possible to readily predict whether
a particular sustained release formulation will provide the desired
sustained release for a soluble to highly soluble drug. It has
generally been found that it is necessary to carry out considerable
experimentation to obtain sustained release formulations providing
the desired bioavailability of such drugs when ingested.
[0013] In order to compensate for the unpredictability associated
with having a controlled release formulation provide the desired
sustained release for a soluble to highly soluble drug, it is
sometimes considered desirable to provide a formulation with
bi-modal or multi-phasic kinetics. Bimodal or multi-phasic release
maybe characterized by an initial high rate followed by a slower
rate as the dosage form passes the upper portion of the small
intestine where absorption is maximum and finally another higher
rate as the dosage form passes into the further end of the
intestine where absorption is less than before.
[0014] Bimodal release is considered to be advantageous for a
number of reasons, including but not limited to the fact that
bimodal release allows the formulator to compensate for changing
absorption rates of the medicament in the gastrointestinal tract by
providing a rapid onset of action (when the formulation is located
in the stomach) and compensate for relatively slow absorption by
providing a relatively rapid release rate (e.g., when the
formulation is located in the large intestine).
[0015] Bimodal release formulations have been provided in a number
of different manners to date.
[0016] For example, International Publication Number WO/87/00044
describes therapeutic formulations which are said to have bimodal
release characteristics. WO 87/00044 describes a carrier base
material for therapeutically active medicaments in a solid dosage
formulation that are said to produce a bimodal controlled release
profile characterized by a rapid initial release of medicament
followed by a substantially constant rate of release for a period
of time, after which the release rate is greater than the constant
rate previously observed. The carrier based material comprises
bimodal hydroxypropylmethylcellulose ethers with a methoxy content
of 19-30%, a hydroxy propoxy content of 4-12%, a viscosity of
40-19,000 cps, an average molecular weight of 20,000-140,000, and
which demonstrates a bimodal release profile in accordance with an
assay method described therein. The bimodal
hydroxypropylmethylcelluloses comprise 5-99% by weight of the total
formulation, depending upon the active ingredient and length of
drug released desire.
[0017] A. C. Shah et al., "Gel-Matrix Systems Exhibiting Bimodal
Controlled Release For Oral Drug Delivery", Journal of Controlled
Release, 9(1989), pp. 169-175, further reported that certain
"types" of hydroxypropylmethylcellulose ethers are found to display
a bimodal drug release profile. However, in that study, series of
hydroxypropylmethylcellulose ether polymers were found to provide
bimodal and non-bimodal release profiles from polymer-drug matrix
tablets, which results appeared to depend upon the supplier of the
polymer (and therefore upon, e.g., the method of manufacture, ionic
composition, variations in the distribution of substituent groups,
or distribution of molecular weight fractions).
[0018] P. Giunchedi et al., "Ketoprofen Pulsatile Absorption From
`Multiple Unit` Hydrophilic Matrices" International Journal of
Pharmaceutics, 77(1991), pp 177-181 described an extended release
oral formulation of Ketoprofen comprising a multiple unit
formulation constituted by four hydrophilic matrices of identical
composition, each containing 50 mg of drug and prepared with
hydroxypropylmethylcellulose (Methocel.RTM.) and placed in a
gelatin capsule. Pulsatile plasma levels (2 peaks at 2nd and 8th
hours after dosing) were said to be obtained, whereas in vitro
tests resulted in a fairly constant drug release.
[0019] U. Conte et al., "A New Ibuprofen Pulsed Release Oral Dosage
Form", Drug. Development And Industrial Pharmacy, 15(14-16), pp
2583-2596 (1989) reported that a pulsed released pattern was
obtained from a 3-layer tablet wherein two layers contained a dose
of drug, and an intermediate layer acted as a control element
separating the drug layers. The control element was a mixture of
water-swellable polymers (hydroxypropylmethylcel- luloses). An
outer film of an impermeable polymer coated the tablet. A
superdisintegrant (sodium starch glycolate and cross-linked
polyvinyl pyrrolidone) was included in the drug layers.
[0020] K. A. Kahn et al, "Pharmaceutical Aspects And In-Vivo
Performance Of Brufen Retard--An Ibuprofen SR Matrix Tablet",
Proced. Intern. Symp. Control. Rel. Bioact. Mater., 18(1991),
Controlled Release Society, Inc., describes a formulation
containing 800 mg of ibuprofen which is said to provide a bimodal
release pattern. The release retarding agent utilized therein was
xanthan gum. The ingredients were blended to the appropriate
xanthan gum content, and thereafter compressed into tablets and
film coated. The amount of xanthan gum included inversely affected
the rate of drug release. An increase in drug particle size or
quantity of film-coat per tablet did not significantly effect the
rate of drug release. Although an increase in particle size of the
xanthan gum caused a more pronounced burst effect, the application
of the film-coat overcame this burst effect. The rapid initial
release of the medicament was hypothesized to be related to changes
in the formation of the gel layer, wherein larger particles gel
more slowly and are sloughed off before a coherent matrix can
form.
[0021] In our U.S. Pat. Nos. 4,994,276, 5,128,143, and 5,135,757,
hereby incorporated by reference, we reported that a controlled
release excipient which is comprised of synergistic heterodisperse
polysaccharides (e.g., a heteropolysaccharide such as xanthan gum
in combination with a polysaccharide gum capable of cross-linking
with the heteropolysaccharide, such as locust bean gum) is capable
of processing into oral solid dosage forms using either direct
compression, following addition of drug and lubricant powder,
conventional wet granulation, or a combination of the two. The
release of the medicament from the formulations therein proceeded
according to zero-order or first-order mechanisms.
[0022] Our own U.S. Pat. No. 5,472,711 and 5,478,574, hereby
incorporated by reference, we report a formulation capable of
providing multi-phasic or bi-phasic controlled release of a
therapeutically active medicament in vitro by incorporating an
effective amount of a pharmaceutically acceptable surfactant with
the above-referenced excipient.
[0023] An example of a highly soluble drug used in the present
invention is diltiazem, which is a benzothiazine derivative
possessing calcium antagonist activity. Diltiazem is widely used in
the treatment of hypertension and angina. Accordingly, a great deal
of attention has been given to the preparation of sustained release
diltiazem which provides an acceptable release profile.
[0024] For example U.S. Pat. Nos. 4,894,240 and 5,364,620
(Geoghegan, et al.) describe a diltiazem pellet formulation
suitable for once daily administration. This formulation comprises
a diltiazem core in association with an organic acid, surrounded by
an insoluble multi-layer membrane. The membrane allows the release
of diltiazem from the pellet at a rate allowing controlled
absorption over a 24 hour period following administration.
[0025] Other techniques have been described in the prior art for
preparing sustained release diltiazem formulations. For example,
U.S. Pat. No. 5,419,917, (Chen et al.) describes a composition
which controls the rate of release of diltiazem from a hydrogel
using a pharmaceutically effective ionizable compound.
[0026] Another example of a highly soluble drug used in the present
invention is oxybutynin. Oxybutynin is widely used in the treatment
of urological disorders, e.g., hyperactive bladder. Our own U.S.
Pat. No. 5,399,359 discloses an oxybutynin sustained release
formulation comprising a pharmaceutically effective amount of
oxybutynin dispersed within a sustained release matrix comprising a
gelling agent, an effective amount of a pharmaceutically acceptable
water-soluble cationic cross-linking agent which cross-links with
the gelling agent when the formulation is exposed to an
environmental fluid, e.g., gastrointestinal fluid, and an inert
diluent.
OBJECTS AND SUMMARY OF THE INVENTION
[0027] It is an object of the present invention to provide a
bioavailable sustained release formulation for soluble to highly
soluble therapeutically active medicaments.
[0028] It is a further object of the present invention to provide a
formulation which can provide multi-phasic or bi-phasic controlled
release for soluble to highly soluble medicaments.
[0029] It is a further object of the present invention to provide a
method for preparing a bioavailable sustained release formulation
for soluble to highly soluble therapeutically active
medicaments.
[0030] It is yet another object of the present invention to provide
a sustained release matrix which may be used in the preparation of
a sustained release oral solid dosage form of soluble to highly
soluble therapeutically active medicaments.
[0031] It is a further object of the present invention to provide a
sustained release matrix which is suitable for providing, when
combined with a medicament, a sustained release formulation which
provides therapeutically effective blood levels of the medicament
for e.g., 12 or 24 hours.
[0032] It is a further object of the invention to provide a
diltiazem sustained release matrix formulation which provides a
plasma profile similar to commercially available sustained release
formulations, e.g., Cardizem CD.
[0033] It is a further object of the invention to provide a
oxybutynin sustained release matrix formulation which provides a
plasma profile similar to commercially available sustained release
formulations, e.g., Ditropan XL.
[0034] The above-mentioned objects and others are achieved by
virtue of the present invention, which relates in part to the
surprising discovery that the incorporation of a pH modifying agent
into a dosage form comprising a gelling agent, facilitates the
release of the drug from the dosage form and provides a high
bioavailability.
[0035] In certain embodiments, the sustained release oral solid
dosage form comprises a therapeutically effective amount of a
medicament having a solubility of more than about 10 g/l; a pH
modifying agent; and a sustained release matrix comprising a
gelling agent, the gelling agent comprising a heteropolysaccharide
gum and a homopolysaccharide gum capable of cross-linking the
heteropolysaccharide gum when exposed to an environmental fluid.
Preferably, the dosage form provides a sustained release of the
medicament for at least about 12 hours, preferably at least about
24 hours.
[0036] In certain embodiments, the dosage form further comprises a)
a pharmaceutically acceptable surfactant which can provide a
multi-phasic release of the drug; b) an inert diluent selected
from, e.g., a monosaccharide, a disaccharide, a polyhydric alcohol,
or mixtures thereof; c) a hydrophobic material to slow the
hydration of the gelling agent; and/or d) an effective amount of a
pharmaceutically acceptable ionizable gel strength enhancing agent
suitable for modifying the release rate from the gel which is
formed when the controlled release formulation is exposed to an
environmental fluid. In a preferred embodiment, the formulation of
the present invention comprises a tablet.
[0037] In a preferred embodiment of the invention, the ratio of
medicament to gelling agent is preferably from about 10:1 to about
1:10, more more preferably from about 5:1 to about 1:5, and most
preferably from about 1.25:1 to about 2:1.
[0038] The present invention is also related to a method for
providing a sustained release formulation of a medicament having
high solubility in water, comprising preparing a matrix comprising
a gelling agent comprising a heteropolysaccharide gum and a
homopolysaccharide gum capable of cross-linking said
heteropolysaccharide gum when exposed to an environmental fluid; an
optional ionizable gel strength enhancing agent, an optionally
inert pharmaceutical diluent; and an optional hydrophobic material,
and thereafter adding a soluble to highly soluble medicament, a pH
modifying agent and an optional pharmaceutically acceptable
surfactant. Thereafter the resulting mixture is tableted such that
a product is obtained having a ratio of medicament to gelling agent
from about 10:1 to about 1:10, more preferably from about 5:1 to
about 1:5, and most preferably from about 1.25:1 to about 2:1, such
that a gel matrix is created when the tablet is exposed to an
environmental fluid and such that the tablets each contain a
therapeutically effective amount of the medicament. The resulting
tablet provides therapeutically effective blood levels of the
medicament for at least about 12 hours, and preferably about 24
hours.
[0039] The present invention is further related to a method of
treating a patient by orally administering an oral solid dosage
form as set forth above.
[0040] In certain preferred embodiments of the invention, the
matrix can be prepared from a pre-granulated sustained release
excipient comprising, e.g. from about 10 to about 99% by weight of
a gelling agent, from about 0 to about 20% by weight of an
ionizable gel strength enhancing agent, from about 1 to about 89%
by weight of an inert pharmaceutical diluent, and from about 1 to
about 20% of a hydrophobic material.
[0041] In other preferred embodiments the mixture of the matrix and
inert diluent are granulated before the addition of the medicament,
with a dispersion or solution of the hydrophobic material in an
amount sufficient to slow the hydration of the matrix without
disrupting the same.
[0042] In other preferred embodiments of the invention, a first
portion of the medicament is introduced during the granulation of
the excipient, and a second portion of the drug is introduced
extragranularly, or after the granulation step. Such an embodiment
provides an initial rapid release of the medicament.
[0043] In preferred embodiments, the medicament is highly soluble,
i.e., has a solubility of more than about 100 g/l.
[0044] In other preferred embodiment, the medicament comprises a
calcium channel blocker, preferably a benzothiazine, most
preferably diltiazem or a pharmaceutically acceptable salt
thereof.
[0045] In other preferred embodiments, the medicament comprises an
antispasmodic, preferably oxybutynin or a pharmaceutically
acceptable salt thereof.
[0046] By "sustained release" it is meant for purposes of the
present invention that the therapeutically active medicament is
released from the formulation at a controlled rate such that
therapeutically beneficial blood levels (but below toxic levels) of
the medicament are maintained over an extended period of time,
e.g., at least about 12 hour or at least about 24 hours.
[0047] By "bioavailable" it is meant for purposes of the present
invention that the therapeutically active medicament is absorbed
from the sustained release formulation and becomes available in the
body at the intended site of drug action, preferably within 80% of
a reference standard (based on comparison of the AUC).
[0048] By "soluble", it is meant that the therapeutically active
medicament has an aqueous solubility of more than about 10 grams
per liter (g/l).
[0049] By "highly soluble", it is meant that the therapeutically
active medicament has an aqueous solubility of more than about 100
grams per liter (g/l).
[0050] The term "environmental fluid" is meant for purposes of the
present invention to encompass, e.g., an aqueous solution, or
gastrointestinal fluid.
[0051] The term "pH modifying agent" is meant for purposes of the
present invention to mean any substance which decreases the
ionization of the medicament, whereby the release of the drug from
the hydrogel matrix and into solution is facilitated.
[0052] The term "Cmax" is meant for purposes of the present
invention to mean then maximum plasma concentration of a medicament
achieved after administration of a dosage form in accordance with
the invention.
[0053] The term "Tmax" is meant for purposes of the present
invention to mean the elapsed time from administration of a dosage
form to the time the Cmax of the medicament is achieved
[0054] The term "W.sub.50".sup.1 is meant for purposes of the
present invention to mean the time period measured by the width of
the plasma concentration curve at 50% of the height of the
Cmax.
[0055] For purposes of the present invention, the dosage form can
have bi-modal kinetics, and accordingly, there can be multiple
Cmaxs, Tmaxs and W.sub.50s for the disclosed dosage forms.
BRIEF DESCRIPTION OF THE DRAWINGS
[0056] The following drawings are illustrative of embodiments of
the invention and are not meant to limit the scope of the invention
as encompassed by the claims.
[0057] FIG. 1 is a graphical representation of the dissolution
(mean percent dissolved over time) for Examples 1 and 2.
[0058] FIG. 2 is a graphical representation of the dissolution
(mean percent dissolved over time) for Examples 3 and 4.
[0059] FIG. 3 is a graphical representation of the dissolution
(mean percent dissolved over time) for Examples 5 and 6.
[0060] FIG. 4 is a graphical representation of the dissolution
(mean percent dissolved over time) for Examples 7 and 8.
[0061] FIG. 5 is a graphical representation of the dissolution
(mean percent dissolved over time) for Examples 9 and 10.
[0062] FIG. 6 is a graphical representation of the dissolution
(mean percent dissolved over time) for Examples 11 and 12.
[0063] FIG. 7 is a graphical representation of the % release rate
over time for Examples 11 and 12.
[0064] FIG. 8 is a graphical representation of the dissolution
(mean percent dissolved over time) for Examples 13 and 18.
[0065] FIG. 9 is a graphical representation of the dissolution
(mean percent dissolved over time) for Examples 19 and 20.
[0066] FIG. 10 is a graphical representation of the dissolution
(mean percent dissolved over time) for Examples 21-23.
[0067] FIG. 11 is a graphical representation of the mean plasma
diltiazem concentration (ng/ml) over time for Example 24 and for a
reference standard (Cardizem CD 240 mg).
[0068] FIG. 12 is a graphical representation of the mean plasma
diltiazem concentration (ng/ml) over time for Examples 25 and for a
reference standard (Cardizem CD 240 mg).
[0069] FIG. 13 is a graphical representation of the dissolution
(mean percent dissolved over time) for Examples 26 and 27.
[0070] FIG. 14 is a graphical representation comparing the
dissolution (mean percent dissolved over time) of Example 37 and
for a reference standard (Ditropan XL).
DETAILED DESCRIPTION
[0071] The sustained release matrix of the present invention can be
a heterodisperse excipient (as previously reported in our U.S. Pat.
Nos. 4,994,276, 5,128,143, and 5,135,757) which can comprise a
gelling agent of both hetero- and homo-polysaccharides which
exhibit synergism, e.g., the combination of two or more
polysaccharide gums produce a higher viscosity and faster hydration
than that which would be expected by either of the gums alone, the
resultant gel being faster-forming and more rigid.
[0072] The term "heteropolysaccharide" as used in the present
invention is defined as a water-soluble polysaccharide containing
two or more kinds of sugar units, the heteropolysaccharide having a
branched or helical configuration, and having excellent
water-wicking properties and immense thickening properties.
[0073] An especially preferred heteropolysaccharide is xanthan gum,
which is a high molecular weight (>10.sup.6)
heteropolysaccharide. Other preferred heteropolysaccharides include
derivatives of xanthan gum, such as deacylated xanthan gum, the
carboxymethyl ether, and the propylene glycol ester.
[0074] The homopolysaccharide gums used in the present invention
which are capable of cross-linking with the heteropolysaccharide
include the galactomannans, i.e., polysaccharides which are
composed solely of mannose and galactose. Galactomannans which have
higher proportions of unsubstituted mannose regions have been found
to achieve more interaction with the heteropolysaccharide. Locust
bean gum, which has a higher ratio of mannose to the galactose, is
especially preferred as compared to other galactomannans such as
guar and hydroxypropyl guar.
[0075] The controlled release properties of the controlled release
formulations of the present invention maybe optimized when the
ratio of heteropolysaccharide gum to homopolysaccharide material is
about 1:1.5, although heteropolysaccharide gum in an amount of from
about 10 to about 90 percent or more by weight of the
heterodisperse polysaccharide material provides an acceptable slow
release product. The combination of any homopolysaccharide gums
known to produce a synergistic effect when exposed to aqueous
solutions may be used in accordance with the present invention. It
is also possible that the type of synergism which is present with
regard to the gum combination of the present invention could also
occur between two homogeneous or two heteropolysaccharides. Other
acceptable gelling agents which may be used in the present
invention include those gelling agents well-known in the art.
Examples include vegetable gums such as alginates, carrageenan,
pectin, guar gum, modified starch, hydroxypropylmethylcellulose,
methylcellulose, and other cellulosic materials such as sodium
carboxymethylcellulose and hydroxypropyl cellulose. This list is
not meant to be exclusive.
[0076] The inert diluent of the sustained release excipient
preferably comprises a pharmaceutically acceptable saccharide,
including a monosaccharide, a disaccharide, or a polyhydric
alcohol, and/or mixtures of any of the foregoing. Examples of
suitable inert pharmaceutical fillers include sucrose, dextrose,
lactose, microcrystalline cellulose, fructose, xylitol, sorbitol,
starches, mixtures thereof and the like. However, it is preferred
that a soluble pharmaceutical filler such as lactose, dextrose,
sucrose, or mixtures thereof be used. The inert diluent or filler
may alternatively comprise a pre-manufactured direct compression
diluent as set forth below.
[0077] For example, it is possible to dry mix the ingredients of
the sustained release excipient without utilizing a wet granulation
step. This procedure may be utilized, for example, where a wet
granulation is to be accomplished when the active ingredient is
directly added to the ingredients of the sustained release
excipient. On the other hand, this procedure may also be used where
no wet granulation step whatsoever is contemplated. If the mixture
is to be manufactured without a wet granulation step, and the final
mixture is to be tableted, it is preferred that all or part of the
inert diluent comprise a pre-manufactured direct compression
diluent. Such direct compression diluents are widely used in the
pharmaceutical arts, and may be obtained from a wide variety of
commercial sources. Examples of such pre-manufactured direct
compression excipients include Emcocel.RTM. (microcrystalline
cellulose, N.F.), Emdex.RTM. (dextrates, N.F.), and Tab-Fine.RTM.
(a number of direct-compression sugars including sucrose, fructose
and dextrose), all of which are commercially available from Penwest
Pharmaceuticals Co., Patterson, New York). Other direct compression
diluents include Anhydrous lactose (Lactose N.F., anhydrous direct
tableting) from Sheffield Chemical, Union, N.J. 07083; Elcems.RTM.
G-250 (powdered cellulose), N.F.) from Degussa, D-600 Frankfurt
(Main) Germany; Fast-Flo Lactose.RTM. (Lactose, N.F., spray dried)
from Foremost Whey Products, Banaboo, Wis. 53913; Maltrin.RTM.
(Agglomerated maltodextrin) from Grain Processing Corp., Muscatine,
Iowa 52761; Neosorb 60.RTM. (Sorbitol, N.F., direct-compression
from Roquet Corp., 645 5th Ave., New York, N.Y. 10022; Nu-Tab.RTM.
(Compressible sugar, N.F.) from Ingredient Technology, Inc.,
Pennsauken, N.J. 08110; Polyplasdone XL.RTM. (Crospovidone, N.F.,
cross-linked polyvinylpyrrolidone) from GAF Corp., New York, N.Y.
10020; Primojel.RTM. (Sodium starch glycolate, N.F., carboxymethyl
starch) from Generichem Corp., Little Falls, N.J. 07424; Solka
Floc.RTM. (Cellulose floc) from Penwest Pharmaceuticals Co.,
Patterson, N.Y. 10512; Spray-dried lactose.RTM. (Lactose N.F.,
spray dried) from Foremost Whey Products, Baraboo, Wis. 53913 and
DMV Corp., Vehgel, Holland; and Sta-Rx 1500.RTM. (Starch 1500)
(Pregelatinized starch, N.F., compressible) from Colorcon, Inc.,
West Point, Pa. 19486.
[0078] In general, the formulation may be prepared as a directly
compressible diluent, for example, by wet granulating, spray drying
lactose or as a premixed direct compression diluent by art known
methods. For purposes of the present invention, these specially
treated inert diluents will be referred to as "directly
compressible" inert diluents.
[0079] In certain embodiments, the ingredients of the sustained
release excipient can be pre-manufactured. However, in other
embodiments the active drug can be added to the excipient
ingredients and that mixture melt granulated to form a granulation.
Finally, where a surfactant is used, the surfactant comprising the
solubilized or dispersed diltiazem or oxybutynin can be added
directly to the mixture of ingredients.
[0080] In further embodiments of the present invention, the
directly compressible inert diluent which is used in conjunction
with the sustained release pharmaceutical excipient of the present
invention is an augmented microcrystalline cellulose as disclosed
in U.S. patent application Ser. No. 08/370,576, filed Jan. 9, 1995,
and entitled "PHARMACEUTICAL EXCIPIENT HAVING IMPROVED
COMPRESSIBILITY", by J. Staniforth, B. Sherwood and E. Hunter,
hereby incorporated by reference in its entirety. The augmented
microcrystalline cellulose described therein is commercially
available under the tradename "Prosolv" from Penwest
Pharmaceuticals Co.
[0081] An effective amount of a pharmaceutically acceptable
surfactant can also be added to the above-mentioned ingredients of
the excipient, or added at the time the medicament is added, in
order to increase the bioavailability of the medicament. An example
of a suitable surfactant is docusate sodium in an amount up to
about 15% by weight of the solid dosage form. An especially
preferred surfactant is sodium lauryl sulfate in an amount up to
about 15% by weight of the solid dosage form.
[0082] In one embodiment, the surfactant is dissolved in a suitable
solvent such as water, and is thereafter added to the blended
mixture of the sustained release excipient and the medicament. This
allows the surfactant to wet the particles of the excipient such
that when the solvent evaporates the particles of the medicament
which precipitate are tiny and do not aggregate. A granulate of the
medicament and the surfactant is obtained which is preferably
finely and homogeneously dispersed in the excipient.
[0083] In certain embodiments of the present invention, e.g.
wherein the medicament is diltiazem or oxybutynin, the surfactant
is included in an amount e.g., from about 0.1% to about 5%, or from
about 1% to about 15% of the final product, by weight. However, the
upper limit of surfactant included can be higher than 15%. One
limiting factor is that the final product should provide a
pharmaceutically acceptable formulation. For example, in the case
of tablets, the upper limit of the amount of surfactant included is
determined by the production of a pharmaceutically acceptable
tablet, e.g., a tablet which has a friability of less than about 1%
and a hardness of 6-8 kg.
[0084] The surfactants which may be used in the present invention
generally include pharmaceutically acceptable anionic surfactants,
cationic surfactants, amphoteric (amphipathic/amphophilic)
surfactants, and non-ionic surfactants. Suitable pharmaceutically
acceptable anionic surfactants include, for example, monovalent
alkyl carboxylates, acyl lactylates, alkyl ether carboxylates,
N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl
glutamates, fatty acid-polypeptide condensates, sulfuric acid
esters, alkyl sulfates (including sodium lauryl sulfate (SLS)),
ethoxylated alkyl sulfates, ester linked sulfonates (including
docusate sodium or dioctyl sodium succinate (DSS)), alpha olefin
sulfonates, and phosphated ethoxylated alcohols.
[0085] Suitable pharmaceutically acceptable cationic surfactants
include, for example, monoalkyl quaternary ammonium salts, dialkyl
quaternary ammonium compounds, amidoamines, and aminimides.
[0086] Suitable pharmaceutically acceptable amphoteric
(amphipathic/amphophilic) surfactants, include, for example,
N-substituted alkyl amides, N-alkyl betaines, sulfobetaines, and
N-alkyl 6-aminoproprionates.
[0087] Other suitable surfactants for use in conjunction with the
present invention include polyethyleneglycols as esters or ethers.
Examples include polyethoxylated castor oil, polyethoxylated
hydrogenated castor oil, polyethoxylated fatty acid from castor oil
or polyethoxylated fatty acid from castor oil or polyethoxylated
fatty acid from hydrogenated castor oil. Commercially available
surfactants which can be used are known under trade names
Cremophor, Myrj, Polyoxyl 40 stearate, Emerest 2675, Lipal 395 and
PEG 3350.
[0088] The pH modifying agent facilitates the release of the drug
from the matrix and is present from about 1% to about 50%; from
about 1% to about 25% from about 1% to about 15%; or from about 1%
to about 10% by weight of the final dosage form. In preferred
embodiments, the pH modifying agent is an organic acid such as
citric acid, succinic acid, fumaric acid, malic acid, maleic acid,
glutaric acid or lactic acid.
[0089] The ionizable gel strength enhancing agent which is
optionally used in conjunction with the present invention may be
monovalent or multivalent metal cations. The preferred salts are
the inorganic salts, including various alkali metal and/or alkaline
earth metal sulfates, chlorides, borates, bromides, citrates,
acetates, lactates, etc. Specific examples of suitable ionizable
gel strength enhancing agent include calcium sulfate, sodium
chloride, potassium sulfate, sodium carbonate, lithium chloride,
tripotassium phosphate, sodium borate, potassium bromide, potassium
fluoride, sodium bicarbonate, calcium chloride, magnesium chloride,
sodium citrate, sodium acetate, calcium lactate, magnesium sulfate
and sodium fluoride. Multivalent metal cations may also be
utilized. However, the preferred ionizable gel strength enhancing
agent are bivalent. Particularly preferred salts are calcium
sulfate and sodium chloride. The ionizable gel strength enhancing
agent of the present invention are added in an amount effective to
obtain a desirable increased gel strength due to the cross-linking
of the gelling agent (e.g., the heteropolysaccharide and
homopolysaccharide gums). In alternate embodiments, the ionizable
gel strength enhancing agent is included in the sustained release
excipient of the present invention in an amount from about 1 to
about 20% by weight of the sustained release excipient, and in an
amount 0.5% to about 16% by weight of the final dosage form.
[0090] In certain embodiments of the present invention, the
sustained release matrix of the present invention comprises a
sustained release excipient which comprises from about 10 to about
99 percent by weight of a gelling agent comprising a
heteropolysaccharide gum and a homopolysaccharide gum, from about 0
to about 20 percent by weight of an ionizable gel strength
enhancing agent, and from about 1 to about 89 percent by weight of
an inert pharmaceutical diluent. In other embodiments, the
sustained release excipient comprises from about 10 to about 75
percent gelling agent, from about 2 to about 15 percent ionizable
gel strength enhancing agent, and from about 30 to about 75 percent
inert diluent. In yet other embodiments, the sustained release
excipient comprises from about 30 to about 75 percent gelling
agent, from about 5 to about 10 percent ionizable gel strength
enhancing agent, and from about 15 to about 65 percent inert
diluent.
[0091] The sustained release excipient of the present invention
(with or without the optional ionizable gel strength enhancing
agent) may be further modified by incorporation of a hydrophobic
material which slows the hydration of the gums without disrupting
the hydrophilic matrix. This is accomplished in alternate
embodiments of the present invention by granulating the sustained
release excipient with the solution or dispersion of a hydrophobic
material prior to the incorporation of the medicament. The
hydrophobic polymer may be selected from an alkylcellulose such as
ethylcellulose, other hydrophobic cellulosic materials, polymers or
copolymers derived from acrylic or methacrylic acid esters,
copolymers of acrylic and methacrylic acid esters, zein, waxes,
shellac, hydrogenated vegetable oils, and any other
pharmaceutically acceptable hydrophobic material known to those
skilled in the art. The amount of hydrophobic material incorporated
into the sustained release excipient is that which is effective to
slow the hydration of the gums without disrupting the hydrophilic
matrix formed upon exposure to an environmental fluid. In certain
preferred embodiments of the present invention, the hydrophobic
material is included in the sustained release excipient in an
amount from about 1 to about 20 percent by weight. The solvent for
the hydrophobic material may be an aqueous or organic solvent, or
mixtures thereof.
[0092] In embodiments where the sustained release excipient of the
present invention has been pre-manufactured, it is then possible to
blend the same with the medicament, e.g., in a high shear mixer. In
certain especially preferred embodiments, the medicament is a
therapeutically effective benzothiazine which are useful for the
treatment of circulatory disorders and high blood pressure. An
especially preferred dihydropyridine is diltiazem. Useful
formulations of diltiazem generally contain daily doses from about
30 to about 500 mg, preferably from about 120 mg to about 480 mg.
In certain preferred embodiments of the present invention, the
dosage form includes a dosage of diltiazem in an amount of 120 mg,
180 mg, 240 mg, or 300 mg for 24 hour formulations; and a dosage of
diltiazem in an amount of 60 mg, 90 mg and 120 mg for 12 hour
formulations.
[0093] In certain other especially preferred embodiments, the
medicament is oxybutynin which is useful for the treatment of
urological disorders. Useful formulations of oxybutynin generally
contain daily doses from about 2.5 mg to about 50 mg, e.g., from
about 2.5 mg to about 25 mg for 12 hour formulations and from about
5 mg to about 50 mg for 24 hour formulations. In certain preferred
embodiments of the present invention, the dosage form includes a
dosage of oxybutynin in an amount of 5 mg, 10 mg, or 15 mg for 24
hour formulations.
[0094] An effective amount of any generally accepted pharmaceutical
lubricant, including calcium or magnesium soaps is preferably added
to the mixture of ingredients (including medicament) prior to
compression of the mixture into oral solid dosage forms, such as
tablets. An example of a suitable lubricant is magnesium stearate
in an amount of about 0.5 to about 3% by weight of the solid dosage
form. An especially preferred lubricant is sodium stearyl fumarate,
NF, commercially available under the trade name Pruve from Penwest
Pharmaceuticals Co.
[0095] The sustained release excipients of the present invention
have uniform packing characteristics over a range of different
particle size distributions and are capable of processing into the
final dosage form (e.g., tablets) using either direct compression,
following addition of drug and lubricant powder, or conventional
wet granulation.
[0096] The properties and characteristics of a specific excipient
system prepared according to the present invention is dependent in
part on the individual characteristics of the homo and
heteropolysaccharide constituents, in terms of polymer solubility,
glass transition temperatures etc., as well as on the synergism
both between different homo- and heteropolysaccharides and between
the homo and heteropolysaccharides and the inert saccharide
constituent(s) in modifying dissolution fluid-excipient
interactions.
[0097] The combination of the gelling agent (i.e., a mixture of
xanthan gum and locust bean gum) with the inert diluent, with or
without the ionizable gel strength enhancing agent and hydrophobic
polymer, provides a ready-to-use sustained release excipient
product in which a formulator need only blend the desired active
medicament, the pH modifying agent, the surfactant and an optional
lubricant with the excipient before compressing the mixture to form
slow release tablets. The excipient may comprise a physical admix
of the gums along with a soluble excipient such as compressible
sucrose, lactose or dextrose, although it is preferred to granulate
or agglomerate the gums with plain (i.e., crystalline) sucrose,
lactose, dextrose, etc., to form an excipient. The granulate form
has certain advantages including the fact that it can be optimized
for flow and compressibility; it can be tableted, formulated in a
capsule, extruded and spheronized with an active medicament to form
pellets, etc.
[0098] The pharmaceutical excipients prepared in accordance with
the present invention may be prepared according to any
agglomeration technique to yield an acceptable excipient product.
In wet granulation techniques, the desired amounts of the
heteropolysaccharide gum, the homopolysaccharide gum, and the inert
diluent are mixed together and thereafter a moistening agent such
as water, propylene glycol, glycerol, alcohol or the like is added
to prepare a moistened mass. Next, the moistened mass is dried. The
dried mass is then milled with conventional equipment into
granules. Therefore, the excipient product is ready to use.
[0099] The pre-manufactured sustained release excipient is
preferably free-flowing and directly compressible. Accordingly, the
excipient may be mixed in the desired proportion with a
therapeutically active medicament and optional lubricant (dry
granulation). Alternatively, all or part of the excipient may be
subjected to a wet granulation with the active ingredient and
thereafter tableted. When the final product to be manufactured is
tablets, the complete mixture, in an amount sufficient to make a
uniform batch of tablets, is then subjected to tableting in a
conventional production scale tableting machine at normal
compression pressure, i.e. about 2000-1600 lbs/sq in. However, the
mixture should not be compressed to such a degree that there is
subsequent difficulty in its hydration when exposed to gastric
fluid.
[0100] One of the limitations of direct compression as a method of
tablet manufacture is the size of the tablet. If the amount of
active is high a pharmaceutical formulator may choose to wet
granulate the active with other excipients to attain a decent size
tablet with the right compact strength. Usually the amount of
filler/binder or excipients needed in wet granulation is less than
that in direct compression since the process of wet granulation
contributes to some extent toward the desired physical properties
of a tablet.
[0101] When the medicament is diltiazem, the average tablet size
for round tablets is preferably about 300 mg to 750 mg and for
capsule-shaped tablets about 700 mg to 1000 mg.
[0102] The average particle size of the granulated excipient of the
present invention preferably ranges from about 50 microns to about
400 microns and preferably from about 185 microns to about 265
microns. The particle size of the granulation is not narrowly
critical, the important parameter being that the average particle
size of the granules, must permit the formation of a directly
compressible excipient which forms pharmaceutically acceptable
tablets. The desired tap and bulk densities of the granulation of
the present invention are normally between from about 0.3 to about
0.8 g/ml, with an average density of from about 0.5 to about 0.7
g/ml. For best results, the tablets formed from the granulations of
the present invention are from about 5 to about 20 kg hardness. The
average flow of the granulations prepared in accordance with the
present invention are preferably from about 25 to about 40 g/sec.
Tablets compacted using an instrumented rotary tablet machine have
been found to possess strength profiles which are largely
independent of the inert saccharide component. Scanning electron
photomicrographs of largely tablet surfaces have provided
qualitative evidence of extensive plastic deformation on
compaction, both at the tablet surface and across the fracture
surface, and also show evidence of surface pores through which
initial solvent ingress and solution egress may occur.
[0103] In certain embodiments of the invention, the tablet is
coated with a sufficient amount of a hydrophobic polymer to render
the formulation capable of further modifying the release of the
medicament. The hydrophobic polymer which is included in the tablet
coating may be the same or different material as compared to the
hydrophobic polymeric material which is optionally granulated with
the sustained release excipient.
[0104] In other embodiments of the present invention, the tablet
coating may comprise an enteric coating material in addition to or
instead of the hydrophobic polymer coating. Examples of suitable
enteric polymers include cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate,
methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose
succinate, cellulose acetate trimellitate, and mixtures of any of
the foregoing. An example of a suitable commercially available
enteric material is available under the trade name Eudragit.TM.
L30D55.
[0105] In further embodiments, the dosage form may be coated with a
hydrophilic coating in addition to or instead of the
above-mentioned coatings. An example of a suitable material which
may be used for such a hydrophilic coating is
hydroxypropylmethyl-cellulose (e.g., Opadry.RTM. commercially
available from Colorcon, West Point, Pa.).
[0106] The coatings may be applied in any pharmaceutically
acceptable manner known to those skilled in the art. For example,
in one embodiment, the coating is applied via a fluidized bed or in
a coating pan. For example, the coated tablets may be dried, e.g.,
at about 60-70.degree. C. for about 3-4 hours in a coating pan. The
solvent for the hydrophobic polymer or enteric coating may be
organic, aqueous, or a mixture of an organic and an aqueous
solvent. The organic solvents may be, e.g., isopropyl alcohol,
ethanol, and the like, with or without water.
[0107] In additional embodiments of the present invention, a
support platform is applied to the tablets manufactured in
accordance with the present invention. Suitable support platforms
are well known to those skilled in the art. An example of suitable
support platform is set forth, e.g., in U.S. Pat. No. 4,839,177,
hereby incorporated by reference. In that patent, the support
platform partially coats the tablet, and consists of a polymeric
material insoluble in aqueous liquids. The support platform may,
for example, be designed to maintain its impermeability
characteristics during the transfer of the therapeutically active
medicament. The support platform may be applied to the tablets,
e.g., via compression coating onto part of the tablet surface, by
spray coating the polymeric materials comprising the support
platform onto all or part of the tablet surface, or by immersing
the tablets in a solution of the polymeric materials.
[0108] The support platform may have a thickness of, e.g., about 2
mm if applied by compression, and about 10.mu. if applied via
spray-coating or immersion-coating. Generally, in embodiments of
the invention wherein a hydrophobic polymer or enteric coating is
applied to the tablets, the tablets are coated to a weight gain
from about 1 to about 20%, and in certain embodiments preferably
from about 5% to about 10%.
[0109] Materials useful in the hydrophobic coatings and support
platforms of the present invention include derivatives of acrylic
acid (such as esters of acrylic acid, methacrylic acid, and
copolymers thereof) celluloses and derivatives thereof (such as
ethylcellulose), polyvinylalcohols, and the like.
[0110] In certain embodiments of the present invention, the tablet
core includes an additional dose of the medicament included in
either the hydrophobic or enteric coating, or in an additional
overcoating coated on the outer surface of the tablet core (without
the hydrophobic or enteric coating) or as a second coating layer
coated on the surface of the base coating comprising the
hydrophobic or enteric coating material. This may be desired when,
for example, a loading dose of a therapeutically active agent is
needed to provide therapeutically effective blood levels of the
active agent when the formulation is first exposed to gastric
fluid. The loading dose of medicament included in the coating layer
maybe, e.g., from about 10% to about 40% of the total amount of
medicament included in the formulation.
[0111] In preferred embodiments of the invention, the final
formulation provides bi-modal or multi-phasic plasma levels when
the medicament is diltiazem.
[0112] In preferred embodiments, when the medicament is diltiazem,
the formulations of the invention provide a first time to peak
plasma concentration (Tmax #1) of the diltiazem in about 4 to about
10 hours after oral administration of the dosage form to the
patient. In certain preferred embodiments, the first time to peak
plasma concentration occurs from about 6 to about 8 hours after
oral administration. In preferred embodiments, the maximum plasma
concentration of diltiazem at the first Tmax (Cmax #1) is from
about 50 to about 100 ng/ml, per administration of a 240 mg dosage
of diltiazem in an oral sustained release dosage form in accordance
with the invention.
[0113] In further preferred embodiments of the invention, the
sustained release diltiazem formulations provide a second peak
plasma concentration (Cmax #2) which occurs in about 10 to about 16
hours after oral administration of the dosage form to the patient
(Tmax #2). In certain preferred embodiments, the second peak plasma
concentration (Cmax #2) occurs in about 12 to about 14 hours after
oral administration of the dosage form to the patient (Tmax #2). In
preferred embodiments, the maximum plasma concentration of
diltiazem at Cmax #2 is from about 60 to about 90 ng/ml, per 240 mg
diltiazem administered over the 24 hour period.
[0114] In certain preferred embodiments, the sustained release
diltiazem formulations provide a the W.sub.50 of Cmax #1 (defined
for purposes of the present invention as the width of the plasma
concentration curve at 50% of the height of the first Cmax (Cmax
#1), based on a trough taken at the Cmin between Cmax #1 and Cmax
#2) is from about 0.5 to about 4 hours, preferably from about 1 to
about 3 hours.
[0115] In certain preferred embodiments, the sustained release
diltiazem formulations provide a W.sub.50 of Cmax #2 (defined for
purposes of the present invention as the width of the plasma
concentration curve at 50% of the height of the second Cmax (Cmax
#2), based on a the trough taken at the Cmin between Cmax #1 and
Cmax #2) is from about 0.5 to about 8 hours, preferably from about
2 to about 6 hours.
[0116] In certain preferred embodiments, the sustained release
diltiazem formulations of the invention provide a ratio of Cmax #1
to Cmax #2 from about 0.5:1 to about 1.5:1; preferably from about
0.7:1 to about 1.2:1.
[0117] Based on the dosage of diltiazem in the sustained release
oral formulations of the invention, one can easily determine the
Cmax #1, Cmax #2, Tmax #1 and Tmax #2 for different dosages of
diltiazem over a 12 or 24 hour period.
[0118] In certain preferred embodiments of the invention when the
medicament is oxybutynin, the formulation provides a time to peak
plasma concentration (Tmax) of oxybutynin in about 5 to about 15
hours, preferably in about 8 to about 12 hours.
[0119] Examples of soluble to highly soluble medicaments which are
suitable for incorporation in the present invention include
antihistamines (e.g., azatadine maleate, brompheniramine maleate,
carbinoxamine maleate, chlorpheniramine maleate,
dexchlorpheniramine maleate, diphenhydramine hydrochloride,
doxylamine succinate, methdilazine hydrochloride, promethazine,
trimeprazine tartrate, tripelennamine citrate, tripelennamine
hydrochloride and triprolidine hydrochloride); antibiotics (e.g.,
penicillin v potassium, cloxacillin sodium, dicloxacillin sodium,
nafcillin sodium, oxacillin sodium, carbenicillin indanyl sodium,
oxytetracycline hydrochloride, tetracycline hydrochloride,
clindamycin phosphate, clindamycin hydrochloride, clindamycin
palmitate hcl, lincomycin hcl, novobiocin sodium, nitrofurantoin
sodium, metronidazole hydrochloride); antituberculosis agents
(e.g., isoniazid); cholinergic agents (e.g., ambenonium chloride,
bethanecol chloride, neostigmine bromide, pyridostigmine bromide);
antimuscarinics (e.g., anisotropine methylbromide, clidinium
bromide, dicyclomine hydrochloride, glycopyrrolate, hexocyclium
methylsulfate, homatropine methylbrornide, hyoscyamine sulphate,
methantheline bromide, hyoscine hydrobromide, oxyphenonium bromide,
propantheline bromide, tridihexethyl chloride); sympathomimetics
(e.g., bitolterol mesylate, ephedrine, ephedrine hydrochloride,
ephedrine sulphate, orciprenaline sulphate, phenylpropanolamine
hydrochloride, pseudoephedrine hydrochloride, ritodrine
hydrochloride, salbutamol sulphate, terbutaline sulphate);
sympatholytic agents (e.g., phenoxybenzamine hydrochloride);
miscellaneous autonomic drugs (e.g., nicotine); iron preparations
(e.g., ferrous gluconate, ferrous sulphate); haemostatics (e.g.,
aminocaproic acid); cardiac drugs (e.g., acebutolol hydrochloride,
disopyramide phosphate, flecainide acetate, procainamide
hydrochloride, propranolol hydrochloride, quinidine gluconate,
timolol maleate, tocainide hydrochloride, verapamil hydrochloride);
antihypertensive agents (e.g., captopril, clonidine hydrochloride,
hydralazine hydrochloride, mecamylamine hydrochloride, metoprolol
tartrate); vasodilators (e.g., papaverine hydrochloride);
non-steroidal anti-inflammatory agents (e.g., choline salicylate,
magnesium salicylate, meclofenamate sodium, naproxen sodium,
tolmetin sodium); anticonvulsants (e.g., phenobarbital sodium,
phenyloin sodium, troxidone, ethosuximide, valproate sodium);
tranquilizers (e.g., acetophenazine maleate, chlorpromazine
hydrochloride, fluphenazine hydrochloride, prochlorperazine
edisylate, promethazine hydrochloride, thioridazine hydrochloride,
trifluoroperazine hydrochloride, lithium citrate, molindone
hydrochloride, thiothixine hydrochloride); stimulants (e.g.,
benzamphetamine hydrochloride, dextroamphetamine sulphate,
dextroamphetamine phosphate, diethylpropion hydrochloride,
fenfluramine hydrochloride, methamphetamine hydrochloride,
methylphenidate hydrochloride, phendimetrazine tartrate,
phenmetrazine hydrochloride, caffeine citrate); barbiturates (e.g.,
amylobarbital sodium, butabarbital sodium, secobarbital sodium);
sedatives (e.g., hydroxyzine hydrochloride, methprylon);
expectorants (e.g., potassium iodide); antiemetics (e.g.,
benzaquinamide hydrochloride, metoclopropamide hydrochloride,
trimethobenzamide hydrochloride); gastro-intestinal drugs (e.g.,
ranitidine hydrochloride); heavy metal antagonists (e.g.,
penicillamine, penicillamine hydrochloride); antithyroid agents
(e.g., methimazole); genitourinary smooth muscle relaxants (e.g.,
flavoxate hydrochloride); vitamins (e.g., thiamine hydrochloride,
ascorbic acid); unclassified agents (e.g., amantadine
hydrochloride, colchicine, etidronate disodium, leucovorin calcium,
methylene blue, potassium chloride, pralidoxime chloride. This list
is not meant to be exclusive.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0120] The following examples illustrate various aspects of the
present invention. They are not to be construed to limit the claims
in any manner whatsoever.
EXAMPLES 1-2
Effect of Drug:Gum Ratio in Formulation
[0121] In Example 1-2, sustained release excipients in accordance
with the present invention are first prepared, the medicament (in
this case diltiazem) and the pH modifying agent (in this case being
fumaric acid) being added subsequently, and the final mixture then
being tableted.
[0122] The sustained release excipient is prepared by dry blending
the requisite amounts of xanthan gum, locust bean gum, and dextrose
in a high speed mixer/granulator for 3 minutes. While running
choppers/impellers, water is added to the dry blended mixture, and
granulated for another 3 minutes. The granulation is then dried in
a fluid bed dryer to a LOD (loss on drying) of less than about 10%
by weight (e.g., 4-7% LOD). The granulation is then milled using 20
mesh screens and dispensed into a granulator. The ingredients of
the granulations of Examples 1-2 are set forth in Table 1
below:
1TABLE 1 PREPARATION OF SUSTAINED-RELEASE EXCIPIENT Component
Amount (%) - Ex. 1 Amount (%) - Ex. 2 1. Xanthan Gum 20 12 2.
Locust Bean Gum 30 18 3. Dextrose 50 70 4. Water 30 25
[0123] Next, the desired amount of diltiazem, fumaric acid and a
suitable amount of water are mixed for 5 minutes with an impeller
type mixer to form a slurry. The slurry is then added to the
sustained release excipient over a 1 minute interval in the
granulator, with the impeller running on low speed. Next, the
mixture is granulated for 2 minutes with the chopper and impeller
on high speed (additional water and granulation time may be used to
form proper granules). The resultant granules are then dried in a
fluid bed dryer until LOD is less than 5% and milled with hammer
forward at 2000-3600 rpm. The milled granulation is then placed in
a V-Blender with sodium lauryl sulfate and blended for 10 minutes.
A suitable tableting lubricant (Pruv.RTM., sodium stearyl fumarate,
NF, commercially available from Penwest Pharmaceuticals Co. is
added, and the mixture is blended for another 3 minutes. The
resultant granulation is then compressed into tablets using a
capsule shaped punch. This final mixture is tableted to
approximately 768 mg. The ingredients of the tablets of Examples
1-2 are set forth in Table 2 below:
2TABLE 2 TABLET FORMULATION - EXAMPLES 1-2 Component Amount (%)
Amount (mg/tab) 1. Sustained-Release Excipient 52.1 400.0 2.
Diltiazem 31.3 240.0 3. Fumaric Acid 5.2 40.0 4. Sodium Laurel
Sulfate 10.4 80.0 5. Pruv .RTM. (Sodium Stearyl Fumarate) 1.0 8.0
6. Water* 27.5 0.0 *Removed during processing
[0124] The final tablets have a tablet weight of 768.0 mg and a
hardness of 15 Kp.
[0125] Dissolution tests were then carried out on the tablets of
Examples 1-2 in 900 ML water in an automated USP dissolution
apparatus (Paddle type II, 100 rpm), and the amount of drug
released was analyzed via UV analysis. The in-vitro dissolution
results are set forth in FIG. 1 and in Table 3 below.
3TABLE 3 Time (hr) Ex. 1 (% dissolved) Ex. 2 (% dissolved) 0 0.0
0.0 1 13.4 8.3 2 19.0 12.4 4 28.4 18.4 8 40.9 29.0 12 52.3 38.2 16
63.1 44.4 20 70.1 49.9 24 78.2 55.3
[0126] From the results provided in FIG. 1 and Table 3, it is
evident that the rate of release of diltiazem is slower as the
amount of gum in the formulations is increased.
EXAMPLES 3-4
Effect of Gum:Dextrose Ratio
[0127] In Examples 3-4, a sustained release excipient is prepared
in accordance with the procedure set forth in Examples 1 and 2. The
ingredients of the sustained release excipient of Examples 3 and 4
are set forth in table 4 below:
4TABLE 4 Component Amount (%) - Ex. Amount (%) - Ex. 2 1 Xanthan
Gum 12 20 2 Locust Bean Gum 18 30 3 Dextrose 70 50 4 Water* 25 35
*removed during processing
[0128] Thereafter, diltiazem tablets are prepared as follows:
[0129] The desired amount of diltiazem, fumaric acid and the
sustained release excipient are placed in a granulator and mixed
for 3 minutes at low speed. Water is added over a 2 minute interval
while the impeller is running at low speed (additional water and
granulation time may be used to form proper granules). The
resultant granules are then dried in a fluid bed dryer until LOD is
less than 5% and milled with hammer forward at 2000-3000 rpm using
screen #0050. The milled granulation is then placed in a V-Blender
with sodium lauryl sulfate and blended for 10 minutes. A suitable
tableting lubricant (Pruv.RTM., sodium stearyl fumarate, NF,
commercially available from Penwest Pharmaceuticals Co.) is added,
and the mixture is blended for another 5 minutes. The resultant
granulation is then compressed into tablets using a capsule shaped
punch. This final mixture is tableted to approximately 750 mg. The
ingredients of the tablets of Examples 3-4 are set forth in Table 5
below:
5TABLE 5 TABLET FORMULATION - EXAMPLES 3-4 Component Amount (%)
Amount (mg/tab) 1. Sustained-Release Excipient 53.3 400.0 2.
Diltiazem 32.0 240.0 3. Fumaric Acid 8.0 60.0 4. Sodium Laurel
Sulfate 5.3 40.0 5. Pruv .RTM. (Sodium Stearyl Fumarate) 1.3 10.0
6. Water* 27.5 0.0 *Removed during processing
[0130] The final tablets have a tablet weight of 750.0 mg and a
hardness of 15 Kp
[0131] Dissolution tests were then carried out on the tablets of
Examples 3-4 in 250 ML buffer (ph 6) in an automated USP
dissolution apparatus (Paddle type III, 15CPM), and the amount of
drug released was analyzed via UV analysis. The in-vitro
dissolution results are set forth in FIG. 2 and in Table 6
below:
6TABLE 6 Time (hr) Ex. 3 (% dissolved) Ex. 4 (% dissolved) 0 0.0
0.0 1 20.1 14.3 3 36.5 25.2 8 64.7 45.5 12 88.3 57.2 16 102.2 67.4
24 103.6 86.2
[0132] From the results provided in FIG. 2 and Table 6, it is
evident that as the amount of gum relative to the amount of
dextrose is increased, a corresponding decrease in drug release is
observed.
EXAMPLES 5-6
Effect of Surfactant Type
[0133] In Examples 5-6, a sustained release excipient is prepared
accordance with the procedure set forth in Examples 1 and 2. The
ingredients of the sustained release excipient of Examples 5 and 6
are set forth in table 7 below:
7 TABLE 7 Component Amount (%) - Ex. 5-6 1 Xanthan Gum 12 2 Locust
Bean Gum 18 3 Dextrose 70 4 Water* 25 *removed during
processing
[0134] Thereafter, diltiazem tablets are prepared as follow:
[0135] The desired amount of diltiazem, fumaric acid and a suitable
amount of water are mixed for 5 minutes with an impeller type mixer
to form a slurry. The slurry is then added to the sustained release
excipient over a 1 minute interval in the granulator, with the
impeller running on low speed. Next, the mixture is granulated for
2 minutes with the chopper and impeller on high speed (additional
water and granulation time may be used to form proper granules).
The resultant granules are then dried in a fluid bed dryer until
LOD is less than 5% and milled with hammer forward at 2000-3000
rpm. The milled granulation of Example 5 is then placed in a
V-Blender with sodium lauryl sulfate, and the milled granulation of
Example 6 is placed in a V-Blender with docusate sodium and blended
for 10 minutes. A suitable tableting lubricant (Pruv.RTM., sodium
stearyl fumarate, NF, commercially available from Penwest
Pharmaceuticals Co. is then added to each example, and the mixtures
are blended for another 3 minutes. The resultant granulations are
then compressed into tablets using a capsule shaped punch. This
final mixture is tableted to approximately 848 mg. The ingredients
of the tablets of Examples 5-6 are set forth in Table 8 below:
8TABLE 8 TABLET FORMULATION - EXAMPLES 5-6 Amount (%) Amount (%)
Component (Ex. 5) (Ex. 6) 1. Sustained-Release Excipient 47.2 47.2
2. Diltiazem 28.3 28.3 3. Fumaric Acid 14.2 14.2 4. Sodium Laurel
Sulfate 9.4 N/A 5. Docusate Sodium N/A 9.4 6. Pruv .RTM. (Sodium
Stearyl Fumarate) 0.9 0.9 7. Water* 26.5 26.5 Amount Amount
(mg/tab) (mg/tab) Component (Ex. 5) (Ex. 6) 1 Sustained-Release
Excipient 400.0 400.0 2 Diltiazem 240.0 240.0 3 Fumaric Acid 120.0
120.0 4 Sodium Laurel Sulfate 80.0 N/A 5 Docusate Sodium N/A 80.0 6
Pruv .RTM. (Sodium Stearyl Fumarate) 8.0 8.0 *Removed during
processing
[0136] The final tablets have a tablet weight of 848.0 mg. and a
hardness of 15 Kp.
[0137] Dissolution tests were then carried out on the tablets of
Examples 1-2. The dissolution tests were conducted in 900 ML water
in an automated USP dissolution apparatus (Paddle type II, 100
rpm), and the amount of drug released was analyzed via UV analysis.
The in-vitro dissolution results are set forth in FIG. 3 and in
Table 9 below.
9TABLE 9 Time (hr) Ex. 5 (% dissolved) Ex. 6 (% dissolved) 0 0.0
0.0 1 14.0 12.2 2 19.3 18.9 4 31.3 29.8 8 49.5 47.6 12 62.7 61.4 16
77.0 73.0 20 88.5 83.5 24 98.6 89.2
[0138] From the results provided in FIG. 3 and Table 9, it is
evident that the rate of release of diltiazem is similar for
equivalent ratios of sodium lauryl sulfate and docusate sodium.
[0139] However, the formulation did process better with sodium
lauryl sulfate.
EXAMPLES 7-8
Effect of Surfactant Level
[0140] In Examples 7-8, a sustained release excipient is prepared
accordance with the procedure set forth in Examples 1 and 2. The
ingredients of the sustained release excipient of Examples 7 and 8
are set forth in table 10 below:
10 TABLE 10 Component Amount (%) - Ex. 7-8 1. Xanthan Gum 12 2.
Locust Bean Gum 18 3. Dextrose 70 4. Water* 25 *Removed during
processing
[0141] Thereafter, diltiazem tablets are prepared as follows:
[0142] The desired amount of diltiazem, fumaric acid and a suitable
amount of water are mixed for 5 minutes with an impeller type mixer
to form a slurry. The slurry is then added to sustained release
excipient over a 1 minute interval in the granulator, with the
impeller running on low speed. Next, the mixture is granulated for
2 minutes with the chopper and impeller on high speed (additional
water and granulation time may be used to form proper granules).
The resultant granules are then dried in a fluid bed dryer until
LOD is less than 5% and milled with hammer forward at 2000-3000
rpm. The milled granulation is then placed in a V-Blender with
sodium lauryl sulfate and blended for 10 minutes. A suitable
tableting lubricant (Pruv.RTM., sodium stearyl fumarate, NF,
commercially available from Penwest Pharmaceuticals Co. is then
added, and the mixture is blended for another 3 minutes. The
resultant granulation is then compressed into tablets using a
capsule shaped punch. This final mixture is tableted to
approximately 768 mg. The ingredients of the tablets of Examples
7-8 are set forth in Table 11 below:
11TABLE 11 TABLET FORMULATION - EXAMPLES 7-8 Amount (%) Amount (%)
Component (Ex. 7) (Ex. 8) 1. Sustained-Release Excipient 52.1 54.9
2. Diltiazem 31.3 33.0 3. Fumaric Acid 5.2 5.5 4. Sodium Laurel
Sulfate 10.4 5.5 5. Pruv .RTM. (Sodium Stearyl Fumarate) 1.0 1.1 6.
Water* 27.5 27.5 *Removed during processing Amount Amount (mg/tab)
(mg/tab) Component (Ex. 7) (Ex. 8) 1. Sustained-Release Excipient
400.0 400.0 2. Diltiazem 240.0 240.0 3. Fumaric Acid 40.0 40.0 4.
Sodium Laurel Sulfate 80.0 40.0 5. Pruv .RTM. Sodium Stearyl
Fumarate 8.0 8.0
[0143] The final tablets of Example 7 have a tablet weight of 768.0
mg. and a hardness of 15 Kp.
[0144] The final tablets of Example 8 have a tablet weight of 728.0
mg. and a hardness of 15 Kp.
[0145] Dissolution tests were then carried out on the tablets of
Examples 7-8. The dissolution tests were conducted in 900 ML water
in an automated USP dissolution apparatus (Paddle type II, 100
rpm), and the amount of drug released was analyzed via UV analysis.
The results are set forth in FIG. 4 and Table 12 below:
12TABLE 12 Time (hr) Ex. 7 (% Dissolved) Ex. 8 (% Dissolved) 0 0.0
0.0 1 13.4 18.5 2 19.0 28.2 4 28.4 40.1 8 40.9 56.1 12 52.3 67.6 16
63.1 77.7 20 70.1 83.8 24 78.2 90.5
[0146] From the results provided in FIG. 4 and Table 12, it is
evident that the dissolution rate of diltiazem is inversely related
to the surfactant level.
EXAMPLES 9-10
Effect of Fumaric Acid Level
[0147] In Examples 9-10, a sustained release excipient is prepared
accordance with the procedure set forth in Examples 1 and 2. The
ingredients of the sustained release excipient of Examples 9 and 10
are set forth in table 13 below:
13 TABLE 13 Component Amount (%) - Ex. 9-10 1. Xanthan Gum 12 2.
Locust Bean Gum 18 3. Dextrose 70 4. Water* 25 *Removed during
processing
[0148] Thereafter, diltiazem tablets are prepared as follows:
[0149] The desired amount of diltiazem, fumaric acid and a suitable
amount of water are mixed for 5 minutes with an impeller type mixer
to form a slurry. The slurry is then added to sustained release
excipient over a 1 minute interval in the granulator, with the
impeller running on low speed. Next, the mixture is granulated for
2 minutes with the chopper and impeller on high speed (additional
water and granulation time may be used to form proper granules).
The resultant granules are then dried in a fluid bed dryer until
LOD is less than 5% and milled with hammer forward at 2000-3000
rpm. The milled granulation is then placed in a V-Blender with
sodium lauryl sulfate and blended for 10 minutes. A suitable
tableting lubricant (Pruv.RTM., sodium stearyl fumarate, NF,
commercially available from Penwest Pharmaceuticals Co. is then
added, and the mixture is blended for another 3 minutes. The
resultant granulation is then compressed into tablets using a
capsule shaped punch. This final mixture is tableted to
approximately 848 mg. The ingredients of the tablets of Examples
9-10 are set forth in Table 14 below:
14TABLE 14 TABLET FORMULATION - EXAMPLES 9-10 Amount (%) Amount (%)
Component (Ex. 9) (Ex. 10) 1. Sustained-Release Excipient 47.2 52.1
2. Diltiazem 28.3 31.3 3. Fumaric Acid 14.2 5.2 4. Sodium Laurel
Sulfate 9.4 10.4 5. Pruv .RTM. (Sodium Stearyl Fumarate) 0.9 1.0
*Sodium Stearyl Fumarate 6. Water* 26.5 26.5 * Removed during
processing Amount Amount (mg/tab) (mg/tab) Component (Ex. 9) (Ex.
10) 1. Sustained-Release Excipient 400.0 400.0 2. Diltiazem 240.0
240.0 3. Fumaric Acid 120.0 40.0 4. Sodium Laurel Sulfate 80.0 80.0
5. Pruv .RTM.* 8.0 8.0 *Sodium Stearyl Fumarate
[0150] The final tablets in Example 9 have a weight of 848.0 mg.
and a hardness of 15 Kp.
[0151] The final tablets in Example 10 have a weight of 768 mg. and
a hardness of 15 Kp.
[0152] Dissolution tests were then carried out on the tablets of
Examples 9-10. The dissolution tests were conducted in 900 ML water
in an automated USP dissolution apparatus (Paddle type II, 100
rpm), and the amount of drug released was analyzed via UV analysis.
The results are set forth in FIG. 5 and Table 15 below:
15TABLE 15 Time (hr) Ex. 9 (% Dissolved) Ex. 10 (% Dissolved) 0 0.0
0.0 1 14.0 13.4 2 19.3 19.0 4 31.3 28.4 8 49.5 40.9 12 62.7 52.3 16
77.0 63.1 20 88.5 70.1 24 98.6 78.2
[0153] From the results provided in FIG. 5 and Table 15, it is
evident that by increasing the amount of fumaric acid in the
formulation, the release rate increases.
EXAMPLES 11-12
Extra-Granular Addition of Drug
[0154] In Examples 11-12, a sustained release excipient is prepared
accordance with the procedure set forth in Examples 1 and 2. The
ingredients of the sustained release excipient of Examples 11 and
12 are set forth in table 16 below:
16 TABLE 16 Component Amount (%) - Ex. 11-12 1. Xanthan Gum 12 2.
Locust Bean Gum 18 3. Dextrose 70 4. Water* 25 *Removed during
processing
[0155] Thereafter, diltiazem tablets are prepared as follows:
[0156] In Example 11, the desired amount of diltiazem, fumaric acid
and a suitable amount of water are mixed for 5 minutes with an
impeller type mixer to form a slurry. The slurry is then added to
sustained release excipient over a 1 minute interval in the
granulator, with the impeller running on low speed. Next, the
mixture is granulated for 2 minutes with the chopper and impeller
on high speed (additional water and granulation time may be used to
form proper granules). The resultant granules are then dried in a
fluid bed dryer until LOD is less than 5% and milled with hammer
forward at 2000-3000 rpm. The milled granulation is then placed in
a V-Blender with sodium lauryl sulfate and blended for 10 minutes.
A suitable tableting lubricant (Pruv.RTM., sodium stearyl fumarate,
NF, commercially available from Penwest Pharmaceuticals Co. is then
added, and the mixture is blended for another 3 minutes. The
resultant granulation is then compressed into tablets using a
capsule shaped punch. This final mixture is tableted to
approximately 848 mg.
[0157] In Example 12, a portion of diltiazem, fumaric acid and a
suitable amount of water are mixed for 5 minutes with an impeller
type mixer to form a slurry. The slurry is then added to sustained
release excipient over a 1 minute interval in the granulator, with
the impeller running on low speed. Next, the mixture is granulated
for 2 minutes with the chopper and impeller on high speed
(additional water and granulation time may be used to form proper
granules). The resultant granules are then dried in a fluid bed
dryer until LOD is less than 5% and milled with hammer forward at
2000-3000 rpm. The milled granulation is then placed in a V-Blender
with sodium lauryl sulfate and the remaining amount of diltiazem
and blended for 0.10 minutes. A suitable tableting lubricant
(Pruv.RTM., sodium stearyl fumarate, NF, commercially available
from Penwest Pharmaceuticals Co. is then added, and the mixture is
blended for another 3 minutes. The resultant granulation is then
compressed into tablets using a capsule shaped punch. This final
mixture is tableted to approximately 848 mg. The ingredients of the
tablets of Examples 11-12 are set forth in Table 17 below:
17TABLE 17 TABLET FORMULATION - EXAMPLES 11-12 Amount Amount
Component (%) (Ex. 11) (%) (Ex. 12) 1. Sustained-Release Excipient
47.2 47.2 2. Diltiazem (granular) 28.3 18.4 3. Diltiazem
(extragranular) N/A 9.9 4. Fumaric Acid 14.2 14.2 5. Sodium Laurel
Sulfate 9.4 9.4 6. Pruv .RTM. (Sodium Stearyl Fumarate) 0.9 0.9 7.
Water* 26.5 25.0 *Removed during processing Amount Amount (mg/tab)
(mg/tab) Component (Ex. 11) (Ex. 12) 1. Sustained-Release Excipient
400.0 400.0 2. Diltiazem (granular) 240.0 156.0 3. Diltiazem
(extragranular) N/A 84.0 4. Fumaric Acid 120.0 120.0 5. Sodium
Laurel Sulfate 80.0 80.0 6. Pruv .RTM. (Sodium Stearyl Fumarate)
8.0 8.0
[0158] The final tablets of Example 11 have a weight of 848.0 mg.
and a hardness of 15 Kp.
[0159] The final tablets of Example 12 have a weight of 848.0 mg.
and a hardness of 15 Kp.
[0160] Dissolution tests were then carried out on the tablets of
Examples 11-12. The dissolution tests were conducted in 900 ML
water in an automated USP dissolution apparatus (Paddle type II,
100 rpm), and the amount of drug released was analyzed via UV
analysis. The results are set forth in FIG. 6 and Table 18
below:
18TABLE 18 Time (hr) Ex. 11 (% Dissolved) Ex. 12 (% Dissolved) 0
0.0 0.0 1 14.2 32.6 2 19.3 35.5 4 31.3 48.7 8 49.5 66.4 12 62.7
78.5 16 77.0 85.2 20 88.5 89.2 24 98.6 94.6
[0161] From the results provided in FIG. 6 and Table 18, it is
shown that the addition of diltiazem extragranularly produces an
initial burst of approximately 35%. It is evident that the addition
of a percentage of the drug extra-granularly provides an initial
rapid release, as also demonstrated by FIG. 7 which depicts the %
release rate of diltiazem from the dosage forms of Examples 11 and
12 over time.
EXAMPLES 13-18
Effect of Coating tablets With Eudragit L30D55 w/NaOH (Methacrylic
Acid Copolymer Aqueous Dispersion)
[0162] In Examples 13-18, a sustained release excipient is prepared
accordance with the procedure set forth in Examples 1 and 2. The
ingredients of the sustained release excipient of Examples 13-18
are set forth in table 19 below:
19 TABLE 19 Component Amount (%) - Ex. 13-18 1. Xanthan Gum 12 2.
Locust Bean Gum 18 3. Dextrose 70 4. Water* 25 *Removed during
processing
[0163] Thereafter, diltiazem tablets are prepared as follows:
[0164] The desired amount of diltiazem, fumaric acid and the
sustained release excipient are mixed in a granulator for 3 minutes
at low speed. A suitable amount of water is then added over a 2
minute interval with the impeller running at low speed. The
resultant slurry is then granulated for 7.5 minutes with the
chopper and impeller on high speed (additional water and
granulation time may be used to form proper granules). The
resultant granules are then dried in a fluid bed dryer until LOD is
less than 5% and milled with hammer forward at 2000-3000 rpm using
screen #0050. The milled granulation is then placed in a V-Blender
with sodium lauryl sulfate and blended for 10 minutes. A suitable
tableting lubricant (Pruv.RTM., sodium stearyl fumarate, NF,
commercially available from Penwest Pharmaceuticals Co. is then
added, and the mixture is blended for another 5 minutes. The
resultant granulation is then compressed into tablets using a
capsule shaped punch. This final mixture is tableted to
approximately 750 mg.
[0165] The ingredients of the tablets of Examples 13-18 are set
forth in Table 20 below:
20TABLE 20 TABLET FORMULATION - EXAMPLES 13-18 Component Amount (%)
1. Sustained-Release Excipient 53.3 2. Diltiazem (granular) 32.0 3.
Fumaric Acid 8.0 4. Sodium Laurel Sulfate 5.3 5 Pruv .RTM. (Sodium
Stearyl Fumarate) 1.3 6. Water* 27.0 *Removed during processing
Component Amount (mg/tab) 1. Sustained-Release Excipient 400.0 2.
Diltiazem (granular) 240.0 3. Fumaric Acid 60.0 4. Sodium Laurel
Sulfate 40.0 5. Pruv .RTM. (Sodium Stearyl Fumarate) 10.0
[0166] The final tablets have a tablet weight of 750.0 mg. and a
hardness of 15 Kp.
[0167] The core tablets were then coated with an aqueous dispersion
of Eudragit L30D55 w/NaOH, e.g., to a weight gain of 3%, 5%, 7%,
and 9% (Examples 15-18, respectively) based on the weight of the
whole tablet.
[0168] The aqueous dispersion was prepared by the following
procedure:
[0169] 1.0N sodium hydroxide solution is prepared by adding 4.0 g
of sodium hydroxide to 50 ml purified water in a volumetric flask
and stirring for 5-15 minutes. Purified water is then added to the
necessary volume and mixed again.
[0170] The talc suspension is prepared by slowly adding 9.31 g
triethyl citrate to 202.54 g purified water while stirring. While
continuing to stir, 22.2 g talc is added to the container over a 3
minute interval. The container is stirred until a suspension is
formed.
[0171] Eudragit suspension is then prepared by passing the Eudragit
through a #40 mesh sieve and weighing out 294.52 g. Using a
dropper, 1.78 g of 1.0N sodium hydroxide solution is added to the
Eudragit while stirring. The mixture is stirred for 30-60
minutes.
[0172] While stirring the Eudragit suspension, the talc suspension
is added over a 5 minute period and stirred for 30-60 minutes.
[0173] Dissolution tests were carried out on the tablets of
Examples 13-18. The dissolution tests were conducted in 250 ML
buffer (ph 6) in an automated USP dissolution apparatus (Paddle
type III, 15 CPM), and the amount of drug released was analyzed via
UV analysis. The results are set forth in FIG. 8 and Table 21
below:
21TABLE 21 Time Ex. 13 Ex. 14 Ex. 15 (hr) Lot A (no coating) Lot B
(no coating) Lot A (3% coating) 0 0.0 0.0 0.0 1 18.4 18.0 5.4 3
32.6 32.8 16.0 8 59.8 60.2 48.9 12 80.5 77.9 68.2 16 92.3 93.9 89.6
24 93.7 98.4 99.0 Time Ex. 16 Ex. 17 Ex. 18 (hr) Lot B (coating 5%)
Lot B (coating 7%) Lot B (coating 9%) 0 0.0 0.0 0.0 1 1.9 0.4 0.4 3
13.8 11.1 8.9 8 44.1 36.3 27.5 12 63.4 54.4 41.8 16 82.4 77.7 56.8
24 98.3 99.6 84.6
[0174] From the results provided in FIG. 8 and Table 21, it is
evident that as the amount (by weight) of the coating increases,
the release rate decreases.
EXAMPLES 19-20
Effect of Coating Tablets With Eudragit RS30D/RL30D(50/50)
(Ammonio-methacrylic Acid Copolymer Aqueous Dispersion)
[0175] In Examples 19-20, a sustained release excipient is prepared
accordance with the procedure set forth in Examples 1 and 2. The
ingredients of the sustained release excipient of Examples 19 and
20 are set forth in table 22 below:
22 TABLE 22 Component Amount (%) - Ex. 19-20 1. Xanthan Gum 12 2.
Locust Bean Gum 18 3. Dextrose 70 4. Water* 25 *removed during
processing
[0176] Thereafter, diltiazem tablets are prepared as follows:
[0177] The desired amount of diltiazem, fumaric acid and the
sustained release excipient are mixed in a granulator for 3 minutes
at low speed. A suitable amount of water is then added over a 2
minute interval with the impeller running at low speed. The
resultant slurry is then granulated for 6 minutes with the chopper
and impeller on high speed (additional water and granulation time
may be used to form proper granules). The resultant granules are
then dried in a fluid bed dryer until LOD is less than 5% and
milled with hammer forward at 2000-3000 rpm using screen #0050. The
milled granulation is then placed in a V-Blender with sodium lauryl
sulfate and blended for 10 minutes. A suitable tableting lubricant
(Pruv.RTM., sodium stearyl fumarate, NF, commercially available
from Penwest Pharmaceuticals Co. is then added, and the mixture is
blended for another 3 minutes. The resultant granulation is then
compressed into tablets using a capsule shaped punch. This final
mixture is tableted to approximately 50 mg.
[0178] The ingredients of the tablets of Examples 19-20 are set
forth in FIG. 9 and Table 23 below:
23TABLE 23 TABLET FORMULATION - EXAMPLES 19-20 Component Amount (%)
Amount (mg/tb) 1. Sustained-Release Excipient 53.3 400.0 2.
Diltiazem (granular) 32.0 240.0 3. Fumaric Acid 8.0 60.0 4. Sodium
Laurel Sulfate 5.3 40.0 5. Pruv .RTM. (Sodium Stearyl Fumarate) 1.3
10.0 6. Water* 27.0 0.0 *Removed during processing
[0179] The final tablets have a weight of 750.0 mg. and a hardness
of Kp 15.
[0180] The core tablet was then coated with an aqueous dispersion
of Eudragit RS30D/RL30D(50/50) to a weight gain of 8%, based on the
weight of the whole tablet.
[0181] The aqueous dispersion was prepared by the following
procedure:
[0182] The Eudragit RS/RL suspension is prepared by mixing 100 g of
Eudragit RS with 100 g of Eudragit RL.
[0183] Talc suspension is prepared by slowly adding 12.0 g triethyl
citrate to 338.0 g purified water while stirring. While continuing
to stir, 50.0 g talc is added to the container over a 3 minute
interval. The container is stirred until a suspension is
formed.
[0184] While stirring the Eudragit suspension, the talc suspension
is then added over a 5 minute period. The resultant mixture is
stirred for 30-60 minutes and screened through a 40 mesh sieve.
[0185] Dissolution tests were carried out on the tablets of
Examples 19-20. The dissolution tests were conducted in 900 ML of
0.1N HCL in an automated USP dissolution apparatus (Paddle type II,
100 rpm), and the amount of drug released was analyzed via UV
analysis. The results are set forth in FIG. 9 and Table 24
below:
24TABLE 24 Time (hr) Ex. 19 (8% coating) Ex. 20 (No coating) 0 0.0
0.0 1 21.5 0.5 3 41.3 11.6 5 55.9 24.4 8 74.3 46.4 10 84.8 57.5 12
91.9 64.9 14 95.1 72.2 16 96.2 77.6 20 96.0 87.5 24 96.1 91.3
[0186] From the results provided in FIG. 9 and Table 24, it is
evident that the coating-decreased the release rate.
EXAMPLES 21-23
Effect of Coating Tablets With Ethylcellulose
[0187] In Examples 21-23, a sustained release excipient is prepared
accordance with the procedure set forth in Examples 1 and 2. The
ingredients of the sustained release excipient of Examples 21-23
are set forth in table 25 below:
25 TABLE 25 Component Amount (%) - Ex. 21-23 1. Xanthan Gum 12 2.
Locust Bean Gum 18 3. Dextrose 70 4. Water* 25 *Removed during
processing
[0188] Thereafter, diltiazem tablets are prepared as follows:
[0189] The desired amount of diltiazem, fumaric acid and the
sustained release excipient are mixed in a granulator for 3 minutes
at low speed. A suitable amount of water is then added over a 2
minute interval with the impeller running at low speed. The
resultant slurry is then granulated for 3 minutes with the chopper
and impaler on high speed (additional water and granulation time
may be used to form proper granules). The resultant granules are
then dried in a fluid bed dryer until LOD is less than 5% and
milled with hammer forward at 2000-3000 rpm using screen #0050. The
milled granulation is then placed in a V-Blender with sodium lauryl
sulfate and blended for 10 minutes. A suitable tableting lubricant
(Pruv.RTM., sodium stearyl Fumarate, NF, commercially available
from Penwest Pharmaceuticals Co. is then added, and the mixture is
blended for another 3 minutes. The resultant granulation is then
compressed into tablets using a capsule shaped punch. This final
mixture is tableted to approximately 750 mg.
[0190] The ingredients of the tablets of Examples 21-23 are set
forth in Table 26 below:
26TABLE 26 TABLET FORMULATION - EXAMPLES 21-23 Component Amount (%)
Amount (mg/tab) 1. Sustained-Release Excipient 53.3 400.0 2.
Diltiazem (granular) 32.0 240.0 3. Fumaric Acid 8.0 60.0 4. Sodium
Laurel Sulfate 5.3 40.0 5. Pruv .RTM. (Sodium Stearyl Fumarate) 1.3
10.0 6. Water* 29.0 0.0
[0191] The final tablets have a tablet weight of 750.0 mg. and a
hardness of 15 Kp.
[0192] The core tablet was then coated with an aqueous dispersion
of Ethylcellulose/Opadry (80/20) to a weight gain of 4% and 6%
(Examples 22 and 23, respectively) based on the whole weight of the
tablet. The aqueous dispersion was prepared by the following
procedure:
[0193] First, 60 g of Opadry is mixed with 340 g of water in a
suitable container. While continuing to mix, 944 g Ethylcellulose
is added to the Opadry dispersion. The resultant mixture is stirred
for 30-60 minutes.
[0194] Dissolution tests were then carried out on the tablets of
Examples 1-2. The dissolution tests are conducted in 250 ML of
buffer (ph 6) in an automated USP dissolution apparatus (Paddle
type m, 15 CPM), and the amount of drug released was analyzed via
UV analysis.
[0195] The results are set forth in FIG. 10 and Table 21 below:
27 TABLE 27 Ex. 21 Ex. 22 Ex. 23 Time (hr) (No Coating) (4%
Coating) (6% Coating) 0 0.0 0.0 0.0 1 8.8 4.1 0.5 3 39.1 29.8 2.6 8
69.0 61.2 58.2 12 85.1 86.7 95.5 16 106.6 99.8 101.3 24 107.0 101.9
101.5
[0196] From the results provided in FIG. 10 and Table 27, it is
evident that as the amount of coating increased, the release rate
decreased.
EXAMPLES 24-25
Effect of Excipient Addition Outside Granulation
[0197] In Examples 24-25, a sustained release excipient is prepared
in accordance with the procedure in Examples 1 and 2. The
ingredients of the sustained release excipient of Examples 24 and
25 are set forth in Table 28 below:
28 TABLE 28 Component Amount (%) Ex. 25 Amount (%) Ex. 26 1.
xanthan Gum 12 12 2. Locust Bean Gum 18 18 3. Dextrose 70 70 4.
Water* 25 25 *Removed during processing.
[0198] Next, tablets were manufactured in accordance with the
ingredients of Table 29 and the procedure that follows:
29TABLE 29 (%) mg/tab (%) Component Ex. 24 Ex. 24 Ex. 25 mg/tabEx25
1. Sustained Release 49.2 400.0 53.3 400.0 Excipient 2. Diltiazem
HCL 19.2 156.0 32.0 240.0 (Intragranular) 3. Diltiazem HCI 10.3
84.0 N/A N/A (Extra granular) 4. Fumaric Acid 14.8 120.0 8.0 60.0
5. Surfactant (SLS) 4.9 40.0 5.3 40.0 6. Sodium Stearyl 1.6 13.0
1.3 10.0 Fumarate, NF 7. Water* 27.0 0.0 27.0 0.0 *Removed during
processing
[0199] The final tablets of Example 24 have a tablet weight of
813.0 mg. and a hardness of 15 Kp.
[0200] The final tablets of Example 25 have a tablet weight of
750.0 mg. and a hardness of 15 Kp.
[0201] The procedure for preparing the formulations of Examples
24-25 is a s follows:
[0202] The desired amount of (1), (2), and (4) are dispensed into a
granulator and mixed for 3 minutes at low speed; while running the
impeller at low speed, (7) is added over a 2 minute interval; the
mixture is granulated for 7.5 minutes with the chopper and the
impeller on high speed (additional water and granulation time may
be used to form proper granules); the granulated mixture is dried
in a fluid bed dryer until the LOD is less than 5%; the dried
[0203] granulation is milled with the hammer forward at 2000-3000
rpm using screen #0050; the milled granulation and (5) or (3&5)
are placed in a V-Blender and blended for 10 minutes; (6) is added
to the V-Blender and blended for 5 minutes. The final mixture is
compressed into tablets using a capsule shaped punch.
[0204] The Eudragit.RTM. L30D55 w/NaOH Coating Dispersion was
prepared as follows:
[0205] A. 1.0N Sodium Hydroxide solution was prepared by adding 4.0
g of Sodium Hydroxide to a 100 ml volumetric flask; then 50 ml of
Purified water and a magnetic stir bar were added into the flask
and the contents of the flask were mixed for 5-15 minutes; the stir
bar was removed and the volume was Q.S. and mixed.
[0206] B. Talc suspension was prepared by weighing 202.54 g of
Purified water in a suitable container; 9.31 g of Triethyl Citrate
was slowly added while the Purified water was stirred; then 22.22 g
of Talc was added over a 2 minute interval to the container while
the mixture was stirred (the mixture was stirred until a suspension
formed).
[0207] C. Eudragit.RTM. L30D55 Suspension was prepared by passing
the Eudragit.RTM. L30D55 through a #40 mesh sieve; 294.52 g of
sieved Eudragit.RTM. L30D55 was weighed and placed into a suitable
container; using a dropper, 3.56 g of the 1.0N Sodium Hydroxide
solution (Step A) was added while the mixture was stirred; the
mixture was stirred for 30-60 minutes.
[0208] D. The final Coating Suspension was prepared by stirring the
Eudragit.RTM. L30D55 Suspension (Step C) while Talc suspension
(step B) was added over a 5 minute period; the mixture was stirred
for 30-60 minutes.
[0209] The tablets were coated for a weight gain of 4% based on the
whole weight of the tablet. The tablets were encapsulated by
placing the coated tablets into clear gelatin capsules.
Plasma Profile of Example 24
[0210] In-vivo studies were performed with the tablet of Example 24
using a two way randomized, open label crossover design in healthy
volunteers, 12 subjects for each, and they were dosed in the fasted
state and compared with CARDIZEM CD.RTM.. The results are set forth
in FIG. 11 and in Tablet 30 below:
30TABLE 30 Time (hours) Ex. 24 Fasted (ng/ml) Cardizem-CD Fasted
(ng/ml) 0 0.00 0.00 1 0.65 0.00 2 4.72 0.00 4 31.02 19.65 6 62.45
83.08 7 63.27 60.98 8 65.45 50.79 9 64.20 42.52 10 65.39 38.43 12
77.30 42.56 14 82.86 52.58 15 81.91 56.40 16 80.17 57.48 18 70.09
57.73 20 57.59 51.97 24 42.21 43.48 30 24.82 28.73 36 10.97 12.8 48
2.55 3.78
Ratio
[0211] The ratio of the area are under the curve between Example 24
and CARDIZEM CD.RTM. 240 mg was 1.16:1. The ratio of the average
Cmax between Example 25 and Cardizem CD 240 mg was 1.16:1.
Outcome
[0212] FIG. 11 and Example 24 demonstrated a Bi-Modal plasma level
in-vivo, the CARDIZEM CD.RTM. also demonstrated Bi-Modal plasma
levels by the mixture of two differently processed bead
formulations.
Plasma Profile of Example 25
[0213] In-vivo studies were performed with the tablets of Example
25 using a two way randomized, open label crossover design in
healthy volunteers, 12 subjects for each and they were dosed in the
fasted state and compared with CARDIZEM CD.RTM.. The results set
forth in FIG. 12 and in Table 31 below:
31TABLE 31 Time (hours) EXAMPLE Fasted (ng.backslash.ml)
Cardizem-CD Fasted (ng.backslash.ml) 0 0.00 0.00 1 0.30 0.05 2 6.55
0.40 4 35.43 5.48 6 77.71 66.02 7 76.91 58.31 8 70.88 47.29 9 66.18
39.31 10 64.98 35.51 12 71.90 38.55 14 65.48 41.66 15 62.72 47.32
16 60.60 49.73 18 48.87 51.16 20 38.95 45.75 24 33.10 41.44 30
20.93 28.40 36 10.14 14.88 48 2.52 4.00
[0214] The ratio of the area under the curve between Example 25 and
Cardizem CD 240 mg. was 1.16:1. The ratio of the average Cmax
between Example 25 and Cardizem CD 240 mg.
Outcome
[0215] FIG. 12 and Example 25 demonstrated a Bi-Modal plasma level
in-vivo, CARDIZEM CD.RTM. also demonstrated Bi-Modal plasma levels
by the mixture of two differently processed bead formulations.
EXAMPLES 26 AND 27
Effect of Different Excipients
[0216] In Examples 26 and 27, a sustained release excipient is
prepared in accordance with the procedure set froth in Examples 1
and 3. The ingredients of the sustained release excipient of
Examples 25 and 26 are set forth in Table 32 below:
32TABLE 32 Component (%) Example 26 Example 27 1. Xanthan Gum 12 25
2. Locust Bean Gum 18 25 3. Calcium Sulfate N/A 10 4. Ethyl
Cellulose N/A 5 5. Dextrose 70 35 6. Water* 25 N/A 7. Ethanol* N/A
20 *Removed during processing
Formulation Table 33
[0217] Thereafter, diltiazem tablets ate prepared as follows:
[0218] The desired amount of diltiazem, fumaric acid and the
sustained release excipient are placed in a granulator and mixed
for 3 minutes at low speed. Water is added over a 2 minute interval
while the impeller is running at low speed (additional water and
granulation time may be used to form proper granules). The
resultant granules are then dried in a fluid bed dryer until LOD is
less than %5 and milled with hammer forward at 2000-3000 rpm using
screen #0050. The milled granulation is then placed in a V-Blender
with sodium lauryl sulfate and blended for 10 minutes. A suitable
tableting lubricant (Pruv.RTM., sodium stearyl fumarate, NF,
commercially available from Penwest Pharmaceuticals Co. is added,
and the mixture is blended for another 5 minutes. The resultant
granulation is then compressed into tablets using a capsule shaped
punch. This final mixture is tableted to approximately 750 mg. The
ingredients of the tablets of Examples 26 and 27 are set forth in
Table 33 below:
33TABLE 33 Ex. 26 Ex. 27 Component Ex. 26% mg/tab Ex. 27% mg/tab 1
Sustained Release Excipient 53.3 400.0 53.3 400.0 2 Diltiazem HCI
32.0 240.0 32.0 240.0 3 Fumaric Acid 8.0 60.0 8.0 60.0 4 Surfactant
(SLS) 5.3 40.0 5.3 40.0 5 Sodium Stearyl Fumarate 1.3 0.0 30.0 0.0
6 *Water 27.0 0.0 30.0 0.0 *Removed during processing
[0219] The final tablets in Example 26 have a tablet weight of
750.0 mg. and a hardness of 15 Kp.
[0220] The final tablets in Example 27 have a tablet weight of
750.0 mg. and a hardness of 15 Kp.
[0221] Dissolution tests were then carried out on the tablets of
Example 26 and 27 in 250 ML buffer (pH 6) in an automated USP
dissolution apparatus (Paddle type III, 15CPM), and the amount of
drug released was analyzed via UV analysis. The in-vitro are set
forth in FIG. 13 and Table 34 below:
34TABLE 34 Time (hours) Example 25 (% dissolved) Example 26 (%
dissolved) 0.0 0.0 0.0 1.0 18.4 12.6 3.0 32.6 23.9 8.0 59.8 45.9
12.0 80.5 60.3 16.0 92.3 71.8 24.0 93.7 91.4
Conclusion
[0222] Example 26 had a dissolution profile that was slower than
Example 25.
Outcome
[0223] Dissolution rate can be modified by using different grades
of excipient.
EXAMPLES 28-29
Effect of Gum:Drug Ratio in Formulation
[0224] In Example 28-29, sustained release excipients in accordance
with the present invention are first prepared, the medicament (in
this case oxybutynin) and the pH modifying agent (in this case
being succinic acid) being added subsequently, and the final
mixture then being tableted.
[0225] The sustained release excipient is prepared by dispensing
xanthan gum, locust bean gum dextrose and calcium sulfate into a
high shear mixer/granulator, dispensing ethyl cellulose into a
vessel containing ethanol, dispensing the ethyl cellulose/ethanol
mixture into the xanthan gum, locust bean gum, dextrose, calcium
sulfate mixture and granulating to form proper granules, drying the
mixture in a fluid bed dryer and milling the dried material to form
proper granules. The ingredients of the sustained-release excipient
of Examples 28-29 are set forth in Table 35 below:
35TABLE 35 PREPARATION OF SUSTAINED-RELEASE EXCIPIENT Component
Amount (%) - Ex. 28 Amount (%) - Ex. 29 1. Xanthan Gum 20 15 2.
Locust Bean Gum 30 15 3. Dextrose 40 60 4. Calcium Sulfate 10 10 5.
Water* 20-30 20-30 *Removed during processing.
[0226] Next, the desired amount of oxybutynin and sodium stearyl
fumarate are screened through a 25 mesh sieve, the screened
oxybutynin and sustained release excipient are dispensed into a
V-blender and blended for 10 minutes, the screened sodium stearyl
fumarate is added into the blended mixture of oxybutynin and
sustained-release excipient and blended for an additional 5
minutes, the final blended end product is then compressed into
tablets using a {fraction (5/16)}" round shaped tooling. This final
mixture is tableted to approximately 179.4 mg. The ingredients of
the tablets of Examples 28-29 are set forth in Tables 36 and 37
below:
36TABLE 36 TABLET FORMULATION - EXAMPLE 28 Component Amount (%)
Amount (mg/tab) 1. Sustained Release Excipient 92.9 166.7 2.
Oxybutynin HCL 5.6 10.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet
weight 179.4 Hardness (Kp) 5
[0227]
37TABLE 37 TABLET FORMULATION - EXAMPLE 29 Component Amount (%)
Amount (mg/tab) 1. Sustained Release Excipient 92.9 166.7 2.
Oxybutynin HCL 5.6 10.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet
weight 179.4 Hardness (Kp) 5
[0228] The final tablets have a tablet weight of 179.4.0 mg and a
hardness of 5 Kp.
[0229] Dissolution tests were then carried out on the tablets of
Examples 28-29. The in-vitro dissolution results are set forth in
Table 38 below.
38TABLE 38 Time (hr) Ex. 28 (% dissolved) Ex. 29 (% dissolved) 0.0
0.0 0.0 2.0 44.4 33.6 4.0 67.6 42.5 6.0 86.6 57.4 8.0 103.0 72.5
12.0 108.7 88.9 20.0 108.7 92.8
[0230] The formulation of Example 28 has a drug:gum ratio of 1:5
and the formulation of Example 29 has a drug:gum ratio of 1:8.3.
From the results provided in Table 38, it is evident that the rate
of release of oxybutynin is slower as the drug:gum ratio in the
formulations is increased.
EXAMPLES 30-31
Effect of Gum:Dextrose Ratio
[0231] In Examples 30-31, a sustained release excipient is prepared
in accordance with the procedure set forth in Examples 28 and 29.
The ingredients of the sustained release excipient of Examples 30
and 31 are set forth in Table 39 below:
39TABLE 39 Component Amount (%) Ex. 30 Amount (%) Ex. 31 1 Xanthan
Gum 20 15 2 Locust Bean Gum 30 15 3 Dextrose 40 60 4 Calcium
Sulfate 10 10 5 Water* 20-30 20-30 *Removed during processing
[0232] Thereafter, oxybutynin tablets are prepared as follows:
[0233] The desired amount of oxybutynin and sodium stearyl fumarate
are screened through a mesh sieve, the screened oxybutynin and
sustained release excipient are dispensed into a V-blender and
blended for 10 minutes, the screened sodium stearyl fumarate is
added into the blended mixture of oxybutynin and sustained-release
excipient and blended for an additional 5 minutes, the final
blended end product is then compressed into tablets using a
{fraction (5/16)}" round shaped tooling. This final mixture is
tableted to approximately 179.4 mg. The ingredients of the tablets
of Examples 30-31 are set forth in Tables 40 and 41 below:
40TABLE 40 TABLET FORMULATION - EXAMPLE 30 Component Amount (%)
Amount (mg/tab) 1. Sustained Release Excipient 92.9 166.7 2.
Oxybutynin HCL 5.6 10.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet
weight 179.4 Hardness (Kp) 5
[0234]
41TABLE 41 TABLET FORMULATION - EXAMPLE 31 Component Amount (%)
Amount (mg/tab) 1. Sustained Release Excipient 92.9 166.7 2.
Oxybutynin HCL 5.6 10.0 3. Sodium Stearyl Fumarate 1.5 2.7 Tablet
weight 179.4 Hardness (Kp) 5
[0235] The final tablets have a tablet weight of 17940 mg and a
hardness of 5 Kp.
[0236] Dissolution tests were then carried out on the tablets of
Examples 30-31. The in-vitro dissolution results are set forth in
Table 38 below.
42TABLE 42 Time (hr) Ex. 30 (% dissolved) Ex. 31 (% dissolved) 0.0
0.0 0.0 2.0 44.4 33.6 4.0 67.6 42.5 6.0 86.6 57.4 8.0 103.0 72.5
12.0 108.7 88.9 20.0 108.7 92.8
[0237] From the results provided in Table 42, it is evident that as
the amount of gum relative to the amount of dextrose is increased,
a corresponding decrease in release of oxybutynin is observed.
EXAMPLES 32-35
Effect of Succinic Acid
[0238] In Examples 32-33, a sustained release excipient is prepared
in accordance with the procedure set forth in Examples 28 and 29.
The ingredients of the sustained release excipient of Examples 32
and 33 are set forth in Table 43 below:
43 TABLE 43 Component Amount (%) - Ex. 32-33 1 Xanthan Gum 25 2
Locust Bean Gum 25 3 Dextrose 35 4 Calcium Sulfate 10 5 Ethyl
Cellulose 5 6 Water* 20-30 *Removed during processing
[0239] Thereafter, oxybutynin tablets are prepared as follows:
[0240] The desired amount of succinic acid, oxybutynin and sodium
stearyl fumarate are screened through a 25 mesh sieve, the screened
succinic acid and sustained release excipient are dispensed into a
V-blender and blended for 10 minutes, the screened oxybutynin is
added into the blended mixture of succinic acid and
sustained-release excipient and blended for an additional 5
minutes, the screened sodium stearyl fumarate is added to the
blended mixture of oxybutynin, succinic acid and sustained-release
excipient and blended for an additional 5 minutes, the final
blended end product is then compressed into tablets using a
{fraction (5/16)}" round shaped tooling. The final mixture of
Example 32 is tableted to approximately 251.0 mg and the final
mixture of Example 33 is tableted to approximately 296.0 mg. The
ingredients in Examples 32-33 are set forth in Tables 44 and 45
below:
44TABLE 44 TABLET FORMULATION - EXAMPLE 32 Component Amount (%)
Amount (mg/tab) 1. Sustained Release Excipient 93.2 234.0 2.
Succinic Acid N/A N/A 3. Oxybutynin HCL 6 15.0 4. Sodium Stearyl
Fumarate 0.8 2.0 Tablet weight 251 Hardness (Kp) 8
[0241] The final tablets have a tablet weight of 251.0 mg and a
hardness of 8 Kp.
45TABLE 45 TABLET FORMULATION - EXAMPLE 33 Component Amount (%)
Amount (mg/tab) 1. Sustained Release Excipient 92.9 166.7 2.
Succinic Acid 15.2 45.0 2. Oxybutynin HCL 5.1 15.0 3. Sodium
Stearyl Fumarate 0.7 2.0 Tablet weight 296.0 Hardness (Kp) 8
[0242] The final tablets have a tablet weight of 296.0 mg and a
hardness of 8 Kp.
[0243] Dissolution tests were then carried out on the tablets of
Examples 32-33. The in-vitro dissolution results are set forth in
Table 46 below:
46TABLE 46 Ex. 32 (% dissolved) Ex. 33 (% dissolved) Time (hr) (0%)
(15%) 0.0 0.0 0.0 2.0 1.3 8.9 4.0 2.1 12.9 6.0 4.7 24.0 8.0 11.3
34.0 12.0 25.9 44.0 20.0 43.9 59.5
[0244] From the results provided in Table 46, it is evident that
the addition of Succinic Acid acids in the solubility of the drug
substance, therefore, increasing the release rate.
[0245] In Examples 34-35, a sustained release excipient is prepared
in accordance with the procedure set forth in Examples 28 and 29.
The ingredients of the sustained release excipient of Examples 34
and 35 are set forth in Table 47 below:
47 TABLE 47 Component Amount (%) - Ex. 34-35 1 Xanthan Gum 25 2
Locust Bean Gum 25 3 Dextrose 35 4 Calcium Sulfate 10 5 Ethyl
Cellulose 5 6 Water* 20-30 *Removed during processing
[0246] Thereafter, oxybutynin tablets are prepared as follows:
[0247] The desired amount of sustained-release excipient, succinic
acid, and oxybutynin are dispensed into a granulator. They are dry
mixed for 3 minutes with the impeller at low speed with the chopper
blade in the off position. Water is added over a 1 minute interval,
then the mixture is granulated at high speed for 3 minutes
(additional water and granulation time may be used to form proper
granules). Next, the mixture is dried in a fluid bed dryer until
the LOD is less than 5%. The dried granulation is milled with the
blade forward at 2000-3000 rpm. The milled granulation and sodium
stearyl fumarate are placed into a V-Blender and blended for 10
minutes. The blended mixture is then compressed into tablets using
a {fraction (5/16)}" round shaped tooling. The final mixture of
Example 34 is tableted to approximately 296.0 mg and the final
mixture of Example 35 is tableted to approximately 266.0 mg. The
ingredients in Examples 34-35 are set forth in Tables 48 and 49
below:
48TABLE 48 TABLET FORMULATION - EXAMPLE 34 Component Amount (%)
Amount (mg/tab) 1. Sustained Release Excipient 79.1 234.0 2.
Succinic Acid 15.2 45.0 3. Oxybutynin HCL 5.1 15.0 4. Sodium
Stearyl Fumarate 0.7 2.0 5. Water* 30-45 N/A Tablet weight 296.0
Hardness (Kp) 8 *Removed during processing
[0248] The final tablets have a tablet weight of 296.0.0 mg and a
hardness of 8 Kp.
49TABLE 49 TABLET FORMULATION - EXAMPLE 35 Component Amount (%)
Amount (mg/tab) 1. Sustained Release Excipient 88.0 234.0 2.
Succinic Acid 5.6 15.0 3. Oxybutynin HCL 5.6 15.0 4. Sodium Stearyl
Fumarate 0.8 2.0 5. Water* 30-45 N/A Tablet weight 266.0 Hardness
(Kp) 8 *Removed during processing
[0249] The final tablets have a tablet weight of 266.0 mg and a
hardness of 8 Kp.
[0250] Dissolution tests were then carried out on the tablets of
Examples 34-35. The in-vitro dissolution results are set forth in
Table 50 below:
50TABLE 50 Ex. 32 (% dissolved) Ex. 33 (% dissolved) Time (hr)
(15%) (6%) 0.0 0.0 0.0 2.0 9.2 5.8 4.0 13.7 7.9 6.0 21.2 11.7 8.0
34.2 23.4 12.0 49.1 37.4 18.0 63.9 57.5
[0251] From the results provided in Table 50, it is evident that
the higher the amount of Succinic Acid in the formulation the
faster the release rate.
EXAMPLE 36
Effect of Coating Tablets With Ethylcellulose
(Surelease.RTM.)/Opadry.RTM. (80/20) Aqueous Dispersion
[0252] The procedure for preparing the Ethylcellulose/Opadry.RTM.
coating is as follows:
[0253] First, weigh 340 g of Water in a suitable container, add 60
g of Opadry.RTM., to the water while mixing. Continue to mix. While
mixing the Opadry.RTM. dispersion, add 933 g of Ethylcellulose
dispersion (Surelease.RTM.) and allow to stir for 30-60 minutes.
The final dispersion is used to coat the tablets for a weight gain
of 3-5% based on the whole weight of the tablet.
[0254] In Example 36, a sustained release excipient is prepared in
accordance with the procedure set forth in Examples 28 and 29. The
ingredients of the sustained release excipient of Example 36 is set
forth in Table 51 below:
51 TABLE 51 Component Amount (%) - Ex. 36 1. Xanthan Gum 25 2.
Locust Bean Gum 25 3. Dextrose 35 4. Calcium Sulfate 10 5. Ethyl
Cellulose 5 6. Water* 20-30 *Removed during processing
[0255] Thereafter, oxybutynin tablets are prepared as follows:
[0256] The desired amount of sustained-release excipient, succinic
acid, and oxybutynin are dispensed into a granulator. They are dry
mixed for 3 minutes with the impeller at low speed with the chopper
blade in the off position. Water is added over a 1 minute interval,
then the mixture is granulated at high speed for 3 minutes
(additional water and granulation time may be used to form proper
granules). Next, the mixture is dried in a fluid bed dryer until
the LOD is less than 5%. The dried granulation is milled with the
blade forward at 2000-3000 rpm. The milled granulation and sodium
stearyl fumarate are placed into a V-Blender and blended for 10
minutes. The blended mixture is then compressed into tablets using
a {fraction (5/16)}" round shaped tooling. The final mixture of
Example 36 is tableted to approximately 296.0 mg. The ingredients
in Examples 36 is set forth in Table 52 below:
52TABLE 52 TABLET FORMULATION - EXAMPLE 36 Component Amount (%)
Amount (mg/tab) 1. Sustained Release Excipient 79.1 234.0 2.
Succinic Acid 15.2 45.0 3. Oxybutynin HCL 5.1 15.0 4. Sodium
Stearyl Fumarate 0.7 2.0 5. Water* 30-45 N/A Tablet weight 296.0
Hardness (Kp) 8 *Removed during processing
[0257] The final tablets have a tablet weight of 296.0.0 mg and a
hardness of 8 Kp.
[0258] Dissolution tests were then carried out on the tablets of
Example 36. The in-vitro dissolution results are set forth in Table
53 below:
53 TABLE 53 Time (hr) Ex. 1 Ex. 2 Ex. 3 0.0 0.0 0.0 0.0 2.0 26.8
7.1 1.7 4.0 32.1 10.3 2.8 6.0 35.8 14.9 5.5 8.0 40.1 20.2 9.0 12.0
54.2 27.4 15.1 20.0 72.2 53.2 32.7
[0259] From the results provided in Table 53, it is evident that as
the amount, by weight of coating increased, the release rate
decreased.
EXAMPLE 37
Effect of Fumaric Acid
[0260] In Example 37, a sustained-release excipient is prepared in
accordance with the procedure set forth in Examples 28-29. The
ingredients of the sustained-release excipient of Example 37 is set
forth in Table 54 below:
54 TABLE 54 Component Amount (%) - Ex. 37 1 Xanthan Gum 25 2 Locust
Bean Gum 25 3 Dextrose 35 4 Calcium Sulfate 10 5 Ethyl Cellulose 5
6 Water* 20-30 *Removed during processing
[0261]
55 TABLET FORMULATION - EXAMPLE 37 Component Amount (mg/tab) 1.
Sustained Release Excipient 166.7 2. Oxybutynin HCL 15 3. Fumaric
Acid 30 4. Pruv .RTM. 2 Total (core only) 213.7
[0262] The final tablets have a tablet weight of 213.7 mg.
[0263] Dissolution tests were then carried out on the tablets of
Example 37 in comparison to Ditropan XL. The in-vitro dissolution
results are set forth in Table 55 below:
56TABLE 55 % Dissolved/Released Time (hr) Ditropan XL 149-141 0 0 0
1 1.9 5.9 2 3.5 8.5 4 13.4 15.7 8 36.1 43.50 12 60.7 72.1 18 85.0
86.9 Recovery 98.4 98.0
[0264] Other formulations of Oxybutynin wherein the pH modifying
agent comprises fumaric acid are set forth in Table 56 below:
57 TABLE 56 Component mg/tab (range) or % as noted 1. Sustained
Release Excipient 170-234 mg 2. Fumaric Acid 15-60 mg 3. Oxybutynin
HCL 5, 10, 15 mg 4. Silicon Dioxide 0-2% 5. Sodium Stearyl Fumarate
1-2%
[0265] The examples provided above are not meant to be exclusive.
Many other variations of the present invention would be obvious to
those skilled in the art, and are contemplated to be within the
scope of the appended claims.
* * * * *