U.S. patent application number 13/278787 was filed with the patent office on 2012-04-26 for controlled release compositions comprising a combination of isosorbide dinitrate and hydralazine hydrochloride.
This patent application is currently assigned to ELAN PHARMA INTERNATIONAL LIMITED. Invention is credited to Sharon Hamm, Gurvinder Singh Rekhi, Richard Sidwell.
Application Number | 20120100209 13/278787 |
Document ID | / |
Family ID | 37996647 |
Filed Date | 2012-04-26 |
United States Patent
Application |
20120100209 |
Kind Code |
A1 |
Rekhi; Gurvinder Singh ; et
al. |
April 26, 2012 |
CONTROLLED RELEASE COMPOSITIONS COMPRISING A COMBINATION OF
ISOSORBIDE DINITRATE AND HYDRALAZINE HYDROCHLORIDE
Abstract
The invention relates to a controlled release composition
comprising a combination of isosorbide dinitrate and hydralazine,
such as hydralazine hydrochloride, that in operation delivers the
drug in a pulsed or multi-modal manner for the treatment of angina,
ischaemic heart disease, arterial hypertension and related disease
conditions. Preferably, the isosorbide dinitrate and hydralazine
hydrochloride can be released from the dosage form in an erodable,
diffusion and/or osmotic-controlled release profile.
Inventors: |
Rekhi; Gurvinder Singh;
(Suwanee, GA) ; Sidwell; Richard; (Cumming,
GA) ; Hamm; Sharon; (Atlanta, GA) |
Assignee: |
ELAN PHARMA INTERNATIONAL
LIMITED
COUNTY WESTMEATH
IE
|
Family ID: |
37996647 |
Appl. No.: |
13/278787 |
Filed: |
October 21, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11262672 |
Oct 31, 2005 |
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13278787 |
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Current U.S.
Class: |
424/456 ;
424/484; 424/490; 424/497; 514/248 |
Current CPC
Class: |
A61K 9/5026 20130101;
A61K 31/4745 20130101; A61P 9/10 20180101; A61K 31/403 20130101;
A61K 31/403 20130101; A61K 9/4866 20130101; A61K 31/4745 20130101;
A61K 9/4858 20130101; A61K 9/485 20130101; A61K 9/5078 20130101;
A61K 2300/00 20130101; A61K 31/34 20130101; A61K 9/4825 20130101;
A61K 31/704 20130101; A61K 31/704 20130101; A61K 9/5084 20130101;
A61K 31/58 20130101; A61K 31/502 20130101; A61K 9/4808 20130101;
A61P 9/12 20180101; A61K 31/58 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/456 ;
424/490; 514/248; 424/484; 424/497 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61P 9/12 20060101 A61P009/12; A61P 9/10 20060101
A61P009/10; A61K 31/502 20060101 A61K031/502; A61K 9/52 20060101
A61K009/52 |
Claims
1. A controlled release pharmaceutical composition comprising a
population of isosorbide dinitrate and hydralazine, or a salt or
derivative thereof, -containing particles, wherein at least a
portion of the particles incorporate a modified-release coating or,
alternatively or additionally, a modified-release matrix material,
such that the composition following oral delivery to a subject
delivers the isosorbide dinitrate and hydralazine, or salt or
derivative thereof, in a pulsatile or zero order manner.
2. The composition according to claim 1, wherein the population of
either isosorbide dinitrate or hydralazine particles, or both, have
a protective coating.
3. The composition according to claim 2, wherein the protective
coating material is selected from the group comprising hydrophilic
polymers, hydrophobic polymers, natural polymers, synthetic
polymers and mixtures thereof.
4. The composition according to claim 1, wherein the population of
isosorbide dinitrate and hydralazine particles comprises
modified-release particles.
5. The composition according to claim 1, wherein the population of
particles is an erodable formulation.
6. The composition according to claim 4, wherein said
modified-release particles have a modified-release coating.
7. The composition according to claim 4, wherein said
modified-release particles comprise a modified-release matrix
coating.
8. The composition of claim 1 wherein said modified-release coating
and/or said modified-release matrix material is selected from the
group consisting of hydrophilic polymers, hydrophobic polymers,
natural polymers, synthetic polymers and mixtures thereof.
9. The composition of claim 8 wherein said particles incorporating
a modified-release coating and/or a modified-release matrix
material are combined so that said isosorbide dinitrate and
hydralazine are released by erosion to the surrounding
environment.
10. The composition according to claim 8, wherein at least one
portion of the composition further comprises an enhancer.
11. The composition according to claim 8, wherein the amount of
isosorbide dinitrate and hydralazine contained therein is in an
amount, each, of from about 0.1 mg to about 1 g.
12. The dosage form according to claim 11 comprising a blend of the
particles contained in a hard gelatin or soft gelatin capsule.
13. The dosage form according to claim 12, wherein the particles
are in the form of mini-tablets and the capsule contains a mixture
of the mini-tablets.
14. The dosage form according to claim 13, in the form of a tablet
comprising a layer of compressed isosorbide dinitrate and
hydralazine-containing particles.
15. The dosage form according to claim 14, wherein the isosorbide
dinitrate and hydralazine-containing particles are provided in a
rapidly dissolving dosage form.
16. A method for the treatment of angina, ischaemic heart disease,
arterial hypertension or related disease conditions comprising
administering a therapeutically effective amount of a composition
according to claim 1.
17. A method for the treatment of angina, ischaemic heart disease,
arterial hypertension or related disease conditions comprising
administering a therapeutically effective amount of a composition
according to claim 2.
18. The composition according to claim 1, wherein the particles
incorporating a modified-release coating comprise a pH-dependent
polymer coating which is effective in releasing a pulse of the
active ingredient following a time delay of two to twelve
hours.
19. The composition according to claim 18, wherein the polymer
coating comprises methacrylate copolymers.
20. The composition according to claim 1, wherein the
modified-release coating comprises a mixture of methacrylate and
ammonio methacrylate copolymers in a ratio sufficient to achieve a
pulse of the active ingredient following a time delay.
21. The composition according to claim 20, wherein the ratio of
methacrylate to ammonio methacrylate copolymers is between
approximately 95:5 and 50:50.
23. The composition according to claim 1, wherein the hydralazine
comprises hydralazine hydrochloride.
23. The composition according to claims 1, wherein at least one
portion of the composition further comprises an antioxidant.
24. The composition according to claim 1, wherein at least one
portion of the composition further comprises a chelating agent.
25. The composition according to claim 23 wherein the antioxidant
comprises ascorbic acid or a salt or derivative thereof.
26. The composition according to claim 24, wherein the chelating
agent comprises edetic acid or a salt or derivative thereof.
27. The composition according to claim 24, wherein the chelating
agent comprises citric acid or fumaric acid or any salts or
derivatives thereof.
28. The composition according to claim 1, wherein at least one
portion of the composition further comprises sugar spheres.
29. The composition according to claim 1, wherein at least one
portion of the composition further comprises microcrystalline
cellulose pellets.
30. The dosage form according to claim 14, wherein the hydralazine
comprises hydralazine hydrochloride.
31. The dosage form according to claim 14, wherein the isosorbide
dinitrate comprises isosorbide dinitrate or any active metabolites
thereof.
32. The method according to claim 16, wherein the hydralazine
comprises hydralazine hydrochloride.
33. The method according to claim 16, wherein the isosorbide
dinitrate comprises isosorbide dinitrate or any active metabolites
thereof.
Description
FIELD OF INVENTION
[0001] The present invention relates to novel compositions for the
treatment of patients suffering from angina, ischaemic heart
disease, arterial hypertension and related disease conditions. In
particular, the present invention relates to novel dosage forms for
the controlled delivery of combinations of isosorbide dinitrate and
hydralazine, or a salt or derivative thereof, and methods of
treatment using the same.
BACKGROUND OF INVENTION
[0002] Isosorbide Dinitrate, classified as a vasodilator,
anti-anginal compound, is chemically known as
1,4:3,6-dianhydro-D-glucitol dinitrate; 1,4:3,6-dianhydrosorbitol
2,5-dinitrate; dinitrosorbide; sorbide dinitrate; and sorbide
nitrate. It has a CAS number of 87-33-2. Isosorbide dinitrate has a
chemical formula of C.sub.6H.sub.8N.sub.2O.sub.8, and a molecular
weight of 236.1.
[0003] The chemical structure of isosorbide dinitrate is shown
below:
##STR00001##
[0004] Isosorbide dinitrate is a fine white to ivory-white odorless
crystalline solid. It is sparingly soluble in water (1.0 g/900 ml);
freely soluble in acetone, chloroform, alcohol and ether, and has a
melting point of 70.degree. C. Isosorbide dinitrate is a synthetic
substance prepared from sorbitol. Diluted isosorbide dinitrate is a
mixture of isosorbide dinitrate (usually 20-50%) with lactose,
mannitol, or excipients added to minimize the risk of explosion. It
may contain up to about 1% of a suitable stabilizer such as
ammonium phosphate.
[0005] Isosorbide dinitrate is commercially available, for example,
under the trade names DILATRATE.RTM.-SR (Schwarz Pharma, Milwaukee,
Wis.); ISORDIL.RTM. and ISORDILR TITRADOSE.RTM. (Wyeth Laboratories
Inc., Philadelphia, Pa.); and SORBITRATE.RTM. (Zeneca
Pharmaceuticals, Wilmington, Del.). Isosorbide dinitrate is also
commercially available under such trade names as Cedocard-5,
Cedocard-10, Cedocard-20, Cedocard Retard, Cedocard IV (Tillotts,
UK), Isoket, Isoket 10, Isoket 20, Isoket Retard, Isoket 0.1%
(Schwartz, UK), Isordil, Isordil Tembids (Ayerst, UK), Sorbichew,
Sorbitrate (Stuart, UK), Vascardin (Nicholas, UK), Soni-Slo (Lipha
Rona, UK); Conducil, Corosorbide, Maycor, Sigillum, Surantol,
Vasodilat (Argentina); Carvasin, Isotrate (Australia); Sorbidilat
(Belgium); Coronex (Canada); Risordan (France); Cardis, Corovliss,
IsoMack, Maycor, Nitrol, Nitrosorbon, Sorbidilat, Vermicet
(Germany); Carvasin, Nitrosorbide, (Italy); Directan, Nitrol
(Japan); Isorbid (Mexico); Sorbaugil (Norway, Sweeden); IsoMack,
Myorexon, Sorbidilat (Switzerland); Iso-Bid, Iso-D, Isotrate,
Sorbide, Sorquad, Vasotrate (USA).
[0006] Isosorbide dinitrate is used principally for management of
ischaemic heart disease by reducing the number, duration and
severity of episodes of angina pectoris. It is effective for angina
(e.g., stable effort angina, mixed angina, unstable angina and
vasospastic or variant angina). Isosorbide dinitrate is used in
acute myocardial infarction in control of ischaemic pain, reduction
of elevated blood pressure and in the treatment of pulmonary edema
and congestive cardiac failure. It is also useful in the treatment
of severe hypertension.
[0007] Therapeutic isosorbide dinitrate dosages for adults for
relief of acute attacks of angina, generally range from about 2.5
mg to about 10 mg. For long term management of ischaemic heart
disease dosing ranges from about 30 mg to about 240 mg per day.
Starting doses for the treatment of angina pectoris may be about
2.5 mg to about 10 mg every 2 to 3 hours, with dosages gradually
increased up to about 10 mg to about 40 mg every 6 hours.
[0008] Hydralazine (including its salts, such as hydralazine
hydrochloride) is classified as a vasodilator, antihypertensive
compound. Hydralazine, also known as 1-hydrazinophatalazine; has a
CAS number of 86-54-4. Hydralazine hydrochloride, also known as
1-hydrazinophtalazine hydrochloride; has a CAS number of 304-20-1.
Hydralazine has the chemical structure of C.sub.8H.sub.8N.sub.4,
and hydralazine hydrochloride has the chemical structure of
C.sub.8H.sub.8N.sub.4.HCl.
[0009] The chemical formula of hydralazine and hydralazine
hydrochloride are shown below:
##STR00002##
[0010] Hydralazine hydrochloride has a white to off-white substance
color and is a crystalline powder. It is an odorless to almost
odorless compound. It is soluble in water (1 in 25), slightly
soluble in ethanol (1 in 500) and in methanol; practically
insoluble in ether or chloroform. A 2% solution in water has a pH
of about 3.5 to about 4.2.
[0011] Hydralazine hydrochloride is commercially available from,
for example, Lederle Standard Products of Pearl River, N.Y. and Par
Pharmaceuticals Inc. of Spring Valley, N.Y. Hydralazine
hydrochloride is branded under several trade names, such as
Alphapress, Apresolin, Apresolina, Apresoline, Dralzine,
Hidralazina, Hydralazine Hydrochloride Tablets USP 23, Hydralazine
Injection BP 1993, Hydralazine Tablets BP 1993, Hydrapress,
Hyperphen, Ipolina, Lowpress, Nepresol, Novo-Hylazin, Rolazine,
Slow-Apresoline, and Supress.
[0012] Hydralazine, including its pharmaceutically acceptable salt
forms, e.g., hydralazine hydrochloride, is useful in the treatment
of arterial hypertension (primary; malignant; pulmonary;
pre-eclampsia and eclampsia), congestive heart failure, pulmonary
hypertension in chronic obstructive pulmonary disease, and aortic
regurgitation. Therapeutic dosages for adults range generally from
about 10 mg four times a day for the first 2 to 4 days, increasing
to about 25 mg 4 times a day for the remainder of the first week.
For the subsequent weeks, dosages may be increased up to about 50
mg 4 times a day. For heart failure dosages may range up to about
800 mg daily or more.
[0013] Isosorbide dinitrate and hydralazine hydrochloride
combinations, and/or like compounds, have been disclosed, for
example, in U.S. Pat. No. 4,868,179 to Cohn for "Method of Reducing
Mortality Associated with Congestive Heart Failure Using
Hydralazine and Isosorbide Dinitrate"; U.S. Pat. No. 6,465,463 to
Cohn et al. for "Methods of Treating and Preventing Congestive
Heart Failure with Hydralazine Compounds and Isosorbide Dinitrate
or Isosorbide Mononitrate"; U.S. Pat. No. 6,635,273 to Loscalzo et
al. for "Methods of Treating Vascular Diseases Characterized by
Nitric Oxide Insufficiency"; and United States Patent Application
No. 2004/0204371 to Cohn et al. for "Kits of Hydralazine Compounds
and Isosorbide Dintrate and/or Isosorbide Mononitrate".
[0014] The combination of isosorbide dinitrate and hydralazine
hydrochloride has been developed by Nitromed, Inc. of Lexington,
Mass. under the trade name BiDil.RTM.. The combination has been
reported to provide a synergistic therapeutic effect for patients
over the individual use of each of the active agents. BiDil.RTM. is
generally administered three times a day in dosages of isosorbide
dinitrate/hydralazine hydrochloride, respectively from about
60/112.5 to about 120/225 mg.
[0015] The present invention relates to a composition for the
controlled-release of a combination of isosorbide, including salts,
derivatives and metabolites thereof, such as isosorbide dinitrate,
(referred to herein as "isosorbide dinitrate") and hydralazine, or
salt or derivative thereof, such as hydralazine hydrochloride
(referred to herein as "hydralazine hydrochloride"). In particular,
the present invention relates to a composition that in operation
delivers an active isosorbide dinitrate and hydralazine
hydrochloride combination in a pulsatile or in a constant zero
order release manner. The present invention further relates to
solid oral dosage forms containing such a controlled release
composition. The present invention is particularly applicable for
multiparticulate formulations of a combination product for
isosorbide dinitrate and hydralazine hydrochloride, providing a
twice-a-day or once daily administration. In particular, the
present invention provides immediate-release pellets and/or beads
for isosorbide dinitrate and hydralazine hydrochloride, e.g., using
powder layering technology or standard Glatt Wurster Process, and
sustained-release pellets and/or beads for isosorbide dinitrate and
hydralazine hydrochloride, e.g., using various polymers or
combination of polymers to provide various release rates ranging
from about 6 hours to about 12 hours or about 12 hours to about 24
hours with or without lag time. In one particularly preferred
embodiment, these multiparticulates are encapsulated in a hard
gelatin capsule to give an isosorbide dinitrate content of about 30
mg to about 120 mg and a hydralazine content of about 50 mg to
about 250 mg ranging for about 12 hour to about 24 hour dosing.
Representative proportions of the immediate release (IR) beads vary
from about 10% to about 60%, with representative proportions of
complementary sustained release (SR) beads varying from about 30%
to about 90%. The IR/SR combination may be blended for ease of
manufacture or may be individually dosed with capsules.
Additionally, the multiparticulates manufactured can be tabletted
using suitable excipients to give appropriate isosorbide dinitrate
and hydralazine content, as stated above.
DESCRIPTION OF THE INVENTION
[0016] The plasma profile associated with the administration of a
drug compound may be described as a "pulsatile profile" in which
pulses of high isosorbide dinitrate and hydralazine hydrochloride
concentration, interspersed with low concentration troughs, are
observed. A pulsatile profile containing two peaks may be described
as "bimodal". A pulsatile profile containing two or more peaks may
be described as "multi-modal". Similarly, a composition or a dosage
form which produces such a profile upon administration may be said
to exhibit "pulsed release" of the isosorbide dinitrate and
hydralazine hydrochloride.
[0017] Conventional frequent dosage regimes in which an immediate
release (IR) dosage form is administered at periodic intervals
typically gives rise to a pulsatile plasma profile. In this case, a
peak in the plasma drug concentration is observed after
administration of each IR dose with troughs (regions of low drug
concentration) developing between consecutive administration time
points. Such dosage regimes (and their resultant pulsatile plasma
profiles) have particular pharmacological and therapeutic effects
associated with them. For example, the wash out period provided by
the fall off of the plasma concentration of the active between
peaks has been thought to be a contributing factor in reducing or
preventing patient tolerance to various types of drugs.
[0018] Multiparticulate modified controlled release compositions
similar to those disclosed herein are disclosed and claimed in the
U.S. Pat. Nos. 6,228,398 and 6,730,325 to Devane et al; both of
which are incorporated by reference herein. Additional disclosures
of a spheroidal oral drug absorption system for multiparticulate
drug delivery for controlling the release and absorption rate of
particular active agents are found in U.S. Pat. No. 4,863,742 to
Panoz et al.; U.S. Pat. No. 4,917,899 to Geoghegan et al.; and U.S.
Pat. No. 6,066,339 Stark et al., the disclosures of which are
herein incorporated by reference. Typically this spheroidal oral
drug absorption system includes microshperoidal beads having
representative diameters of from about 0.5 mm to about 2.0 mm, with
each bead providing a miniature controlled absorption system,
allowing individualized release rates for the isosorbide dinitrate
and hydralazine hydrochloride. Such beads may be dispensed in
dispensing systems, such as capsules, sprinkles and tablets.
[0019] Accordingly, it is an object of the present invention to
provide a multiparticulate modified release composition containing
isosorbide dinitrate and hydralazine hydrochloride which in
operation produces a plasma profile substantially similar to the
plasma profile produced by the administration of three or more IR
dosage forms given sequentially.
[0020] It is a further object of the invention to provide a
multiparticulate modified release composition which in operation
delivers isosorbide dinitrate and hydralazine hydrochloride in a
pulsatile manner.
[0021] Another object of the invention is to provide a
multiparticulate modified release composition which substantially
mimics the pharmacological and therapeutic effects produced by the
administration of three or more IR dosage forms given
sequentially.
[0022] Another object of the present invention is to provide a
multiparticulate modified release composition which substantially
reduces or eliminates the development of patient tolerance to
isosorbide dinitrate and hydralazine hydrochloride of the
composition.
[0023] Another object of the invention is to provide a
multiparticulate modified release composition in which a first
portion of an isosorbide dinitrate and hydralazine hydrochloride
combination is released immediately upon administration and a
second portion of the active ingredient is released rapidly after
an initial delay period in a multi-modal manner.
[0024] Another object of the present invention is to formulate the
dosage forms as erodable formulations, diffusion-controlled
formulations, and osmotic-controlled formulations that deliver the
drug in a zero order fashion for about 12 to about 24 hours.
[0025] Another object of the invention is to provide a
multiparticulate modified release composition capable of releasing
isosorbide dinitrate and hydralazine hydrochloride in a bimodal or
multi-modal manner in which a first portion of the active is
released either immediately or after a delay time to provide a
pulse of drug release and one or more additional portions of the
active are released each after a respective lag time to provide
additional pulses of drug release.
[0026] Another object of the invention is to provide solid oral
dosage forms comprising a multiparticulate modified release
composition of the present invention.
[0027] Other objects of the invention include provision of a once
daily dosage form of an isosorbide dinitrate and hydralazine
hydrochloride which, in operation, produces a plasma profile
substantially similar to the plasma profile produced by the
administration of three immediate release dosage forms given
sequentially and a method for treatment of angina, ischaemic heart
disease, arterial hypertension and related disease conditions based
on the administration of such a dosage form.
DETAILED DESCRIPTION OF THE INVENTION
A. Multiparticulate Controlled Release Isosorbide Dinitrate and
Hydralazine Hydrochloride Compositions
[0028] The above objects are realized by a controlled release
composition having a first component comprising a first population
of isosorbide dinitrate and hydralazine hydrochloride, and a second
and subsequent component comprising a second and subsequent
population of isosorbide dinitrate and hydralazine hydrochloride
particles. The ingredient-containing particles of the second and
subsequent component are coated with a modified release coating.
Alternatively or additionally, the second and subsequent population
of isosorbide dinitrate and hydralazine hydrochloride-containing
particles further comprises a modified release matrix material.
Following oral delivery, the composition in operation delivers the
isosorbide dinitrate and hydralazine hydrochloride in a first order
(pulsatile) or zero order manner.
[0029] In a preferred embodiment, the controlled release
composition of the present invention comprises a first component
which is an immediate release component.
[0030] The modified release coating applied to the second and
subsequent population of isosorbide dinitrate and hydralazine
hydrochloride causes a lag time between the release of active from
the first population of active isosorbide dinitrate and hydralazine
hydrochloride-containing particles and the release of active from
the second and subsequent population of active isosorbide dinitrate
and hydralazine hydrochloride-containing particles. Similarly, the
presence of a modified release matrix material in the second and
subsequent populations of active isosorbide dinitrate and
hydralazine hydrochloride-containing particles causes a lag time
between the release of isosorbide dinitrate and hydralazine
hydrochloride from the first population of isosorbide dinitrate and
hydralazine hydrochloride-containing particles and the release of
active ingredient from the second population of active ingredient
containing particles. Similarly, the presence of a modified release
matrix material in the second and subsequent population of active
isosorbide dinitrate and hydralazine hydrochloride-containing
particles causes a lag time between the release of isosorbide
dinitrate and hydralazine hydrochloride from the second population
of isosorbide dinitrate and hydralazine hydrochloride-containing
particles and the release of active ingredient from the third
population of active ingredient containing particles. The duration
of the lag time may be varied by altering the composition and/or
the amount of the modified release coating and/or altering the
composition and/or amount of modified release matrix material
utilized. Thus, the duration of the lag time can be designed to
mimic a desired plasma profile.
[0031] Because the plasma profile produced by the controlled
release composition upon administration is substantially similar to
the plasma profile produced by the administration of two or more IR
dosage forms given sequentially, the controlled release composition
of the present invention is particularly useful for administering
isosorbide dinitrate and hydralazine hydrochloride for which
patient tolerance may be problematical. This controlled release
composition is therefore advantageous for reducing or minimizing
the development of patient tolerance to the active ingredient in
the composition.
[0032] In a preferred embodiment of the present invention,
isosorbide dinitrate and hydralazine hydrochloride and the
composition in operation delivers the isosorbide dinitrate and
hydralazine hydrochloride in a multi-modal pulsatile or zero order
manner. Such a pulsatile composition in operation produces a plasma
profile which substantially mimics that obtained by the sequential
administration of two IR doses as, for instance, that found in a
typical treatment regimen. The present invention further relates to
a controlled release composition comprising isosorbide dinitrate
and hydralazine hydrochloride which in operation produced a plasma
profile that eliminates the "peaks" and "troughs" produced by the
administration of two or more IR dosage forms given sequentially if
such a profile is beneficial. This type of profile can be obtained
using a controlled release mechanism that allows for "zero-order"
delivery.
[0033] The present invention also provides solid oral dosage forms
comprising the novel compositions of the present invention.
[0034] The term "particulate" as used herein refers to a state of
matter which is characterized by the presence of discrete
particles, pellets, beads or granules irrespective of their size,
shape or morphology. The term "multiparticulate" as used herein
means a plurality of discrete or aggregated particles, pellets,
beads, granules or mixture thereof, irrespective of their size,
shape or morphology.
[0035] The term "modified release" as used herein with respect to
the coating or coating material or used in any other context, means
release which is not immediate release and is taken to encompass
controlled release, sustained release and delayed release.
[0036] The term "time delay" as used herein refers to the duration
of time between administration of the composition and the release
of the isosorbide dinitrate and hydralazine hydrochloride from a
particular component.
[0037] The term "lag time" as used herein refers to the time
between delivery of the isosorbide dinitrate and hydralazine
hydrochloride from one component and the subsequent delivery
isosorbide dinitrate and hydralazine hydrochloride from another
component.
[0038] The term "erodable" as used herein refers to formulations
which may be worn away, diminished, or deteriorated by the action
of substances within the body.
[0039] The term "diffusion controlled" as used herein refers to
formulations which may spread as the result of their spontaneous
movement, for example, from a region of higher to one of lower
concentration.
[0040] The term "osmotic controlled" as used herein refers to
formulations which may spread as the result of their movement
through a semi-permeable membrane into a solution of higher
concentration that tends to equalize the concentrations of the
formulation on the two sides of the membrane.
[0041] The active ingredient in each component may be the same or
different. For example, a composition may comprise a first
component containing isosorbide dinitrate and hydralazine
hydrochloride, and the second component may comprise a second
active ingredient which would be desirable for combination
therapies. Indeed, two or more active ingredients may be
incorporated into the same component when the active ingredients
are compatible with each other. A drug compound present in one
component of the composition may be accompanied by, for example, an
enhancer compound or a sensitizer compound in another component of
the composition, in order to modify the bioavailability or
therapeutic effect of the drug compound.
[0042] As used herein, the term "enhancer" refers to a compound
which is capable of enhancing the absorption and/or bioavailability
of an active ingredient by promoting net transport across the GIT
in an animal, such as a human. Enhancers include but are not
limited to medium chain fatty acids; salts, esters, ethers and
derivatives thereof, including glycerides and triglycerides;
non-ionic surfactants such as those that can be prepared by
reacting ethylene oxide with a fatty acid, a fatty alcohol, an
alkylphenol or a sorbitan or glycerol fatty acid ester; cytochrome
P450 inhibitors, P-glycoprotein inhibitors and the like; and
mixtures of two or more of these agents.
[0043] Furthermore, as stated herein, "stabilizers" refers to a
compound which is capable of enhancing the stability of an active
ingredient e.g. stability enhancers, pH modifiers, chelating
agents, antioxidants, free radical sequestrants, etc. . . .
Examples of stabilizers include but are not limited to edetic acid
and salts thereof, citric acid and salts thereof, and ascorbic
acid, fumaric acid and salts thereof.
[0044] The proportion of the isosorbide dinitrate and hydralazine
hydrochloride contained in each component may be the same or
different depending on the desired dosing regime. The isosorbide
dinitrate and hydralazine hydrochloride are present in the first
component and in the second component in any amount sufficient to
elicit a therapeutic response. The isosorbide dinitrate and
hydralazine hydrochloride, when applicable, may be present either
in the form of one substantially optically pure enantiomer or as a
mixture, racemic or otherwise, of enantiomers. The isosorbide
dinitrate and hydralazine hydrochloride are preferably present
individually in a composition in an amount of from about 0.1 to
about 500 mg, preferably in the amount of from about 1 about 100
mg. The isosorbide dinitrate and hydralazine hydrochloride are each
preferably present in the first component in an amount of from
about 0.5 to about 60 mg; more preferably the isosorbide dinitrate
and hydralazine hydrochloride are each present in the first
component in an amount of from about 2.5 to about 30 mg. The
isosorbide dinitrate and hydralazine hydrochloride are present in
the subsequent components in an amount within a similar range to
that described for the first component.
[0045] The time release characteristics for the delivery of the
isosorbide dinitrate and hydralazine hydrochloride from each of the
components may be varied by modifying the composition of each
component, including modifying any of the excipients or coatings
which may be present. In particular, the release of the isosorbide
dinitrate and hydralazine hydrochloride may be controlled by
changing the composition and/or the amount of the modified release
coating on the particles, if such a coating is present. If more
than one modified release component is present, the modified
release coating for each of these components may be the same or
different. Similarly, when modified release is facilitated by the
inclusion of a modified release matrix material, release of the
active ingredient may be controlled by the choice and amount of
modified release matrix material utilized. The modified release
coating may be present, in each component, in any amount that is
sufficient to yield the desired delay time for each particular
component. The modified release coating may be preset, in each
component, in any amount that is sufficient to yield the desired
time lag between components.
[0046] The lag time or delay time for the release of the isosorbide
dinitrate and hydralazine hydrochloride from each component may
also be varied by modifying the composition of each of the
components, including modifying any excipients and coatings which
may be present. For example, the first component may be an
immediate release component wherein the isosorbide dinitrate and
hydralazine hydrochloride are released immediately upon
administration. Alternatively, the first component may be, for
example, a time-delayed immediate release component in which the
isosorbide dinitrate and hydralazine hydrochloride are released
substantially in their entirety immediately after a time delay. The
second and subsequent component may be, for example, a time-delayed
immediate release component as just described or, alternatively, a
time-delayed sustained release or extended release component in
which the isosorbide dinitrate and hydralazine hydrochloride are
released in a controlled fashion over an extended period of
time.
[0047] As will be appreciated by those skilled in the art, the
exact nature of the plasma concentration curve will be influenced
by the combination of all of these factors just described. In
particular, the lag time between the delivery (and thus also the
on-set of action) of the isosorbide dinitrate and hydralazine
hydrochloride in each component may be controlled by varying the
composition and coating (if present) of each of the components.
Thus by variation of the composition of each component (including
the amount and nature of the active ingredient(s)) and by variation
of the lag time, numerous release and plasma profiles may be
obtained. Depending on the duration of the lag time between the
release of the isosorbide dinitrate and hydralazine hydrochloride
from each component and the nature of the release of the isosorbide
dinitrate and hydralazine hydrochloride from each component (i.e.
immediate release, sustained release etc.), the pulses in the
plasma profile may be well separated and clearly defined peaks
(e.g. when the lag time is long) or the pulses may be superimposed
to a degree (e.g. in when the lag time is short).
[0048] In a preferred embodiment, the controlled release
composition according to the present invention has an immediate
release component and at least one modified release component, the
immediate release component comprising a first population of active
ingredient containing particles and the modified release component
comprising second and subsequent populations of active ingredient
containing particles. The second and subsequent modified release
components may comprise a controlled release coating. Additionally
or alternatively, the second and subsequent modified release
components may comprise a modified release matrix material. In
operation, administration of such a multi-particulate modified
release composition having, for example, a single modified release
component results in characteristic pulsatile plasma concentration
levels of the isosorbide dinitrate and hydralazine hydrochloride in
which the immediate release component of the composition gives rise
to a first peak in the plasma profile and the modified release
component gives rise to a second peak in the plasma profile.
Embodiments of the invention comprising more than one modified
release component give rise to further peaks in the plasma
profile.
[0049] Such a plasma profile produced from the administration of a
single dosage unit is advantageous when it is desirable to deliver
two (or more) pulses of active ingredient without the need for
administration of two (or more) dosage units. Additionally, in the
case of treating angina, ischaemic heart disease, arterial
hypertension and related disease conditions, it is particularly
useful to have such a bimodal plasma profile. For example, a
typical isosorbide dinitrate and hydralazine hydrochloride
treatment regime consists of the administration of two doses of an
immediate release dosage formulation given twelve hours apart. This
type of regime has been found to be therapeutically effective and
is widely used. As previously mentioned, the development of patient
tolerance is an adverse effect sometimes associated with isosorbide
dinitrate and hydralazine hydrochloride treatments. It is believed
that the trough in the plasma profile between the two peak plasma
concentrations is advantageous in reducing the development of
patient tolerance by providing a period of wash out of the
isosorbide dinitrate and hydralazine hydrochloride active.
[0050] In addition, a delivery system having a zero order or
pseudo-zero order delivery that eliminates or minimizes the "peak"
to "trough" ratio is also described.
[0051] Any coating material which modifies the release of the
isosorbide dinitrate and hydralazine hydrochloride in the desired
manner may be used. In particular, coating materials suitable for
use in the practice of the present invention include but are not
limited to polymer coating materials, such as cellulose acetate
phthalate, cellulose acetate trimaletate, hydroxy propyl
methylcellulose phthalate, polyvinyl acetate phthalate, ammonio
methacrylate copolymers such as those sold under the Trade Mark
Eudragit.RTM. RS and RL, poly acrylic acid and poly acrylate and
methacrylate copolymers such as those sold under the Trade Mark
Eudragit.RTM. S and L, polyvinyl acetaldiethylamino acetate,
hydroxypropyl methylcellulose acetate succinate, shellac; hydrogels
and gel-forming materials, such as carboxyvinyl polymers, sodium
alginate, sodium carmellose, calcium carmellose, sodium
carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose,
methyl cellulose, gelatin, starch, and cellulose based cross-linked
polymers--in which the degree of crosslinking is low so as to
facilitate adsorption of water and expansion of the polymer matrix,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
polyvinylpyrrolidone, crosslinked starch, microcrystalline
cellulose, chitin, aminoacryl-methacrylate copolymer (Eudragit.RTM.
RS-PM, Rohm & Haas), pullulan, collagen, casein, agar, gum
arabic, sodium carboxymethyl cellulose, (swellable hydrophilic
polymers) poly(hydroxyalkyl methacrylate) (m. wt. about 5 k-5,000
k), polyvinylpyrrolidone (m. wt. about 10 k-360 k), anionic and
cationic hydrogels, polyvinyl alcohol having a low acetate
residual, a swellable mixture of agar and carboxymethyl cellulose,
copolymers of maleic anhydride and styrene, ethylene, propylene or
isobutylene, pectin (m. wt. about 30 k-300 k), polysaccharides such
as agar, acacia, karaya, tragacanth, algins and guar,
polyacrylamides, Polyox(polyethylene oxides (m. wt. about 100
k-5,000 k), AquaKeep (acrylate polymers, diesters of polyglucan,
crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone,
sodium starch glucolate (e.g. Explotab (; Edward Mandell C. Ltd.);
hydrophilic polymers such as polysaccharides, methyl cellulose,
sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl
cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro
cellulose, carboxymethyl cellulose, cellulose ethers, polyethylene
oxides (e.g. Polyox.RTM., Union Carbide), methyl ethyl cellulose,
ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate,
cellulose propionate, gelatin, collagen, starch, maltodextrin,
pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl
acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic
acid, copolymers of methacrylic acid or methacrylic acid (e.g.
Eudragit.RTM., Rohm and Haas), other acrylic acid derivatives,
sorbitan esters, natural gums, lecithins, pectin, alginates,
ammonia alginate, sodium, calcium, potassium alginates, propylene
glycol alginate, agar, and gums such as arabic, karaya, locust
bean, tragacanth, carrageens, guar, xanthan, scleroglucan and
mixtures and blends thereof. As will be appreciated by the person
skilled in the art, excipients such as plasticisers, lubricants,
solvents and the like may be added to the coating. Suitable
plasticisers include for example acetylated monoglycerides; butyl
phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate;
dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin;
propylene glycol; triacetin; citrate; tripropioin; diacetin;
dibutyl phthalate; acetyl monoglyceride; polyethylene glycols;
castor oil; triethyl citrate; polyhydric alcohols, glycerol,
acetate esters, gylcerol triacetate, acetyl triethyl citrate,
dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate,
diisononyl phthalate, butyl octyl phthalate, dioctyl azelate,
epoxidised tallate, triisoctyl trimellitate, diethylhexyl
phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl
phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate,
tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate,
di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl
sebacate.
[0052] When the modified release component comprises a modified
release matrix material, any suitable modified release matrix
material or suitable combination of modified release matrix
materials may be used. Such materials are known to those skilled in
the art. The term "modified release matrix material" as used herein
includes hydrophilic polymers, hydrophobic polymers and mixtures
thereof which are capable of modifying the release of isosorbide
dinitrate and hydralazine hydrochloride dispersed therein in vitro
or in viva Modified release matrix materials suitable for the
practice of the present invention include but are not limited to
microcrystalline cellulose, sodium carboxymethylcellulose,
hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and
hydroxypropylcellulose, polyethylene oxide, alkylcelluloses such as
methylcellulose and ethylcellulose, polyethylene glycol,
polyvinylpyrrolidone, cellulose acteate, cellulose acetate
butyrate, cellulose acteate phthalate, cellulose acteate
trimellitate, polyvinylacetate phthalate, polyalkylmethacrylates,
polyvinyl acetate and mixture thereof.
[0053] A controlled release composition according to the present
invention may be incorporated into any suitable dosage form which
facilitates release of the active ingredient in a pulsatile or zero
order manner. Typically, the dosage form may be a blend of the
different populations of isosorbide dinitrate and hydralazine
hydrochloride-containing particles which make up the immediate
release and the modified release components, the blend being filled
into suitable capsules, such as hard or soft gelatin capsules.
Alternatively, the different individual populations of active
ingredient containing particles may be compressed (optionally with
additional excipients) into mini-tablets which may be subsequently
filled into capsules in the appropriate proportions. Another
suitable dosage form is that of a multilayer tablet. In this
instance the first component of the controlled release composition
may be compressed into one layer, with the second component being
subsequently added as a second layer of the multilayer tablet. The
populations of isosorbide dinitrate and hydralazine
hydrochloride-containing particles making up the composition of the
invention may further be included in rapidly dissolving dosage
forms such as an effervescent dosage form or a fast-melt dosage
form.
[0054] The composition according to the invention comprises at
least two populations of isosorbide dinitrate and hydralazine
hydrochloride-containing particles which have different in-vitro
dissolution profiles.
[0055] Preferably, in operation the composition of the invention
and the solid oral dosage forms containing the composition release
the isosorbide dinitrate and hydralazine hydrochloride such that
substantially all of the isosorbide dinitrate and hydralazine
hydrochloride contained in the first component is released prior to
release of the isosorbide dinitrate and hydralazine hydrochloride
from the second component. When the first component comprises an
immediate release (IR) component, for example, it is preferable
that release of the isosorbide dinitrate and hydralazine
hydrochloride from the second component is delayed until
substantially all the isosorbide dinitrate and hydralazine
hydrochloride in the IR component has been released. Release of the
isosorbide dinitrate and hydralazine hydrochloride from the second
component may be delayed as detailed above by the use of a modified
release coating(s) and/or a modified release matrix material.
[0056] More preferably, when it is desirable to minimize patient
tolerance by providing a dosage regime which facilitates wash-out
of a first dose of the isosorbide dinitrate and hydralazine
hydrochloride from a patient's system, release of the isosorbide
dinitrate and hydralazine hydrochloride from the second and
subsequent component is delayed until substantially all of the
isosorbide dinitrate and hydralazine hydrochloride contained in the
first component has been released, and further delayed until at
least a portion of the isosorbide dinitrate and hydralazine
hydrochloride released from the first component has been cleared
from the patient's system. In a preferred embodiment, release of
the isosorbide dinitrate and hydralazine hydrochloride from the
second component of the composition in operation is substantially,
if not completely, delayed for a period of at least about two hours
after administration of the composition.
[0057] The isosorbide dinitrate and hydralazine hydrochloride
release of the drug from the second component of the composition in
operation is substantially, if not completely, delayed for a period
of at least about six hours, preferably about twelve hours, after
administration of the composition.
B. Other Types of Controlled Release Isosorbide Dinitrate and
Hydralazine Hydrochloride Compositions
[0058] As described herein, the invention includes various types of
controlled release systems by which the active drug may be
delivered in a pulsatile or zero order manner. These systems
include, but are not limited to: films with the drug in a polymer
matrix (monolithic devices); the drug contained by the polymer
(reservoir devices); polymeric colloidal particles or
microencapsulates (microparticles, microspheres or nanoparticles)
in the form of reservoir and matrix devices; drug contained by a
polymer containing a hydrophilic and/or leachable additive e.g., a
second polymer, surfactant or plasticizer, etc. to give a porous
device, or a device in which the drug release may be osmotically
"controlled" (both reservoir and matrix devices); enteric coatings
(ionizable and dissolve at a suitable pH); (soluble) polymers with
(covalently) attached `pendant` drug molecules; devices where
release rate is controlled dynamically: e.g., the osmotic pump.
[0059] The delivery mechanism of the present invention will control
the rate of release of the drug. While some mechanisms will release
the drug at a constant rate (zero order), others will vary as a
function of time depending on factors such as changing
concentration gradients or additive leaching leading to porosity,
etc.
[0060] Polymers used in sustained release coatings are necessarily
biocompatible, and ideally biodegradable. Examples of both
naturally occurring polymers such as Aquacoat.RTM. (FMC
Corporation, Food & Pharmaceutical Products Division,
Philadelphia, USA) (ethylcellulose mechanically spheronised to
sub-micron sized, aqueous based, pseudo-latex dispersions), and
also synthetic polymers such as the Eudragit.RTM. (Rohm Pharma,
Weiterstadt) range of poly(acrylate, methacrylate) copolymers are
known in the art.
[0061] 1. Reservoir Devices
[0062] A typical approach to controlled release is to encapsulate
or contain the drug entirely (e.g., as a core), within a polymer
film or coat (i.e., microcapsules or spray/pan coated cores).
[0063] The various factors that can affect the diffusion process
may readily be applied to reservoir devices (e.g., the effects of
additives, polymer functionality {and, hence, sink-solution pH}
porosity, film casting conditions, etc.) and, hence, the choice of
polymer must be an important consideration in the development of
reservoir devices. Modeling the release characteristics of
reservoir devices (and monolithic devices) in which the transport
of the drug is by a solution-diffusion mechanism therefore
typically involves a solution to Fick's second law (unsteady-state
conditions; concentration dependent flux) for the relevant boundary
conditions. When the device contains dissolved active agent, the
rate of release decreases exponentially with time as the
concentration (activity) of the agent (i.e., the driving force for
release) within the device decreases (i.e., first order release).
If, however, the active agent is in a saturated suspension, then
the driving force for release is kept constant (zero order) until
the device is no longer saturated. Alternatively the release-rate
kinetics may be desorption controlled, and a function of the square
root of time.
[0064] Transport properties of coated tablets, may be enhanced
compared to free-polymer films, due to the enclosed nature of the
tablet core (permeant) which may enable the internal build-up of an
osmotic pressure which will then act to force the permeant out of
the tablet.
[0065] The effect of de-ionized water on salt containing tablets
coated in poly(ethylene glycol) (PEG)-containing silicone
elastomer, and also the effects of water on free films has been
investigated. The release of salt from the tablets was found to be
a mixture of diffusion through water filled pores, formed by
hydration of the coating, and osmotic pumping. KCl transport
through films containing just 10% PEG was negligible, despite
extensive swelling observed in similar free films, indicating that
porosity was necessary for the release of the KCl which then
occurred by `trans-pore diffusion.` Coated salt tablets, shaped as
disks, were found to swell in de-ionized water and change shape to
an oblate spheroid as a result of the build-up of internal
hydrostatic pressure: the change in shape providing a means to
measure the `force` generated. As might be expected, the osmotic
force decreased with increasing levels of PEG content. The lower
PEG levels allowed water to be imbibed through the hydrated
polymer; whilst the porosity resulting from the coating dissolving
at higher levels of PEG content (about 20 to about 40%) allow the
pressure to be relieved by the flow of KCl.
[0066] Methods and equations have been developed, which by
monitoring (independently) the release of two different salts
(e.g., KCl and NaCl) allowed the calculation of the relative
magnitudes that both osmotic pumping and trans-pore diffusion
contributed to the release of salt from the tablet. At low PEG
levels, osmotic flow was increased to a greater extent than was
trans-pore diffusion due to the generation of only a low pore
number density: at a loading of 20%, both mechanisms contributed
approximately equally to the release. The build-up of hydrostatic
pressure, however, decreased the osmotic inflow, and osmotic
pumping. At higher loadings of PEG, the hydrated film was more
porous and less resistant to outflow of salt. Hence, although the
osmotic pumping increased (compared to the lower loading),
trans-pore diffusion was the dominant release mechanism. An osmotic
release mechanism has also been reported for microcapsules
containing a water soluble core.
[0067] 2. Monolithic Devices (Matrix Devices)
[0068] Monolithic (matrix) devices are possibly the most common of
the devices for controlling the release of drugs. This is possibly
because they are relatively easy to fabricate, compared to
reservoir devices, and there is not the danger of an accidental
high dosage that could result from the rupture of the membrane of a
reservoir device. In such a device the active agent is present as a
dispersion within the polymer matrix, and they are typically formed
by the compression of a polymer/drug mixture or by dissolution or
melting. The dosage release properties of monolithic devices may be
dependent upon the solubility of the drug in the polymer matrix or,
in the case of porous matrixes, the solubility in the sink solution
within the particle's pore network, and also the tortuosity of the
network (to a greater extent than the permeability of the film),
dependent on whether the drug is dispersed in the polymer or
dissolved in the polymer. For low loadings of drug, (0 to 5% W/V)
the drug will be released by a solution-diffusion mechanism (in the
absence of pores). At higher loadings (5 to 10% W/V), the release
mechanism will be complicated by the presence of cavities formed
near the surface of the device as the drug is lost: such cavities
fill with fluid from the environment increasing the rate of release
of the drug.
[0069] It is common to add a plasticiser (e.g., a poly(ethylene
glycol)), a surfactant, or adjuvant (i.e., an ingredient which
increases effectiveness), to matrix devices (and reservoir devices)
as a means to enhance the permeability (although, in contrast,
plasticizers may be fugitive, and simply serve to aid film
formation and, hence, decrease permeability--a property normally
more desirable in polymer paint coatings). It was noted that the
leaching of PEG increased the permeability of (ethyl cellulose)
films linearly as a function of PEG loading by increasing the
porosity, however, the films retained their barrier properties, not
permitting the transport of electrolyte. It was deduced that the
enhancement of their permeability was as a result of the effective
decrease in thickness caused by the PEG leaching. This was
evidenced from plots of the cumulative perminant flux per unit area
as a function of time and film reciprocal thickness at a PEG
loading of 50% W/W: plots showing a linear relationship between the
rate of permeation and reciprocal film thickness, as expected for a
(Fickian) solution-diffusion type transport mechanism in a
homogeneous membrane. Extrapolation of the linear regions of the
graphs to the time axis gave positive intercepts on the time axis:
the magnitude of which decreased towards zero with decreasing film
thickness. These changing lag times were attributed to the
occurrence of two diffusional flows during the early stages of the
experiment (the flow of the `drug` and also the flow of the PEG),
and also to the more usual lag time during which the concentration
of permeant in the film is building-up. Caffeine, when used as a
permeant, showed negative lag times. No explanation of this was
forthcoming, but it was noted that caffeine exhibited a low
partition coefficient in the system, and that this was also a
feature of aniline permeation through polyethylene films which
showed a similar negative time lag.
[0070] The effects of added surfactants on (hydrophobic) matrix
devices has been investigated. It was thought that surfactant may
increase the drug release rate by three possible mechanisms: (i)
increased solubilization, (ii) improved `wettability` to the
dissolution media, and (iii) pore formation as a result of
surfactant leaching. For the system studied (Eudragit.RTM. RL 100
and RS 100 plasticised by sorbitol, Flurbiprofen as the drug, and a
range of surfactants) it was concluded that improved wetting of the
tablet led to only a partial improvement in drug release (implying
that the release was diffusion, rather than dissolution,
controlled), although the effect was greater for Eudragit.RTM. RS
than Eudragit.RTM. RL, whilst the greatest influence on release was
by those surfactants that were more soluble due to the formation of
`disruptions` in the matrix allowing the dissolution medium access
to within the matrix. This is of obvious relevance to a study of
latex films which might be suitable for pharmaceutical coatings,
due to the ease with which a polymer latex may be prepared with
surfactant as opposed to surfactant-free. Differences were found
between the two polymers--with only the Eudragit.RTM. RS showing
interactions between the anionic/cationic surfactant and drug. This
was ascribed to the differing levels of quaternary ammonium ions on
the polymer.
[0071] Composite devices consisting of a polymer/drug matrix coated
in a polymer containing no drug also exist. Such a device was
constructed from aqueous Eudragit.RTM. latices, and was found to
give zero order release by diffusion of the drug from the core
through the shell. Similarly, a polymer core containing the drug
has been produced, but coated this with a shell that was eroded by
the gastric fluid. The rate of release of the drug was found to be
relatively linear (a function of the rate limiting diffusion
process through the shell) and inversely proportional to the shell
thickness, whereas the release from the core alone was found to
decrease with time.
[0072] 3. Microspheres
[0073] Methods for the preparation of hollow microspheres
(`microballoons`) with the drug dispersed in the sphere's shell,
and also highly porous matrix-type microspheres (`microsponges`)
have been described. The microsponges were prepared by dissolving
the drug and polymer in ethanol. On addition to water, the ethanol
diffused from the emulsion droplets to leave a highly porous
particle.
[0074] The hollow microspheres were formed by preparing a solution
of ethanol/dichloro-methane containing the drug and polymer. On
pouring into water, this formed an emulsion containing the
dispersed polymer/drug/solvent particles, by a coacervation-type
process, from which the ethanol (a good solvent for the polymer)
rapidly diffused precipitating polymer at the surface of the
droplet to give a hard-shelled particle enclosing the drug,
dissolved in the dichloromethane. At this point, a gas phase of
dichloromethane was generated within the particle which, after
diffusing through the shell, was observed to bubble to the surface
of the aqueous phase. The hollow sphere, at reduced pressure, then
filled with water, which could be removed by a period of drying.
(No drug was found in the water.) A suggested use of the
microspheres was as floating drug delivery devices for use in the
stomach.
[0075] 4. Pendent Devices
[0076] A means of attaching a range of drugs such as analgesics and
antidepressants, etc., by means of an ester linkage to
poly(acrylate) ester latex particles prepared by aqueous emulsion
polymerization has been developed. These latices when passed
through an ion exchange resin such that the polymer end groups were
converted to their strong acid form could `self-catalyse` the
release of the drug by hydrolysis of the ester link.
[0077] Drugs have been attached to polymers, and also monomers have
been synthesized with a pendent drug attached. The research group
have also prepared their own dosage forms in which the drug is
bound to a biocompatible polymer by a labile chemical bond
polyanhydrides prepared from a substituted anhydride (itself
prepared by reacting an acid chloride with the drug: methacryloyl
chloride and the sodium salt of methoxy benzoic acid) were used to
form a matrix with a second polymer (Eudragit.RTM. RL) which
released the drug on hydrolysis in gastric fluid. The use of
polymeric Schiff bases suitable for use as carriers of
pharmaceutical amines has also been described.
[0078] 5. Enteric Films
[0079] Enteric coatings consist of pH sensitive polymers. Typically
the polymers are carboxylated and interact (swell) very little with
water at low pH, whilst at high pH the polymers ionize causing
swelling, or dissolving of the polymer. Coatings can therefore be
designed to remain intact in the acidic environment of the stomach
(protecting either the drug from this environment or the stomach
from the drug), but to dissolve in the more alkaline environment of
the intestine.
[0080] 6. Osmotically Controlled Devices
[0081] The osmotic pump is similar to a reservoir device but
contains an osmotic agent (eg, the active agent in salt form) which
acts to imbibe water from the surrounding medium via a
semi-permeable membrane. Such a device, called the `elementary
osmotic pump`, has been described. Pressure is generated within the
device which forces the active agent out of the device via an
orifice (of a size designed to minimize solute diffusion, whilst
preventing the build-up of a hydrostatic pressure head which has
the effect of decreasing the osmotic pressure and changing the
dimensions {volume} of the device). Whilst the internal volume of
the device remains constant, and there is an excess of solid
(saturated solution) in the device, then the release rate remains
constant delivering a volume equal to the volume of solvent
uptake.
[0082] 7. Electrically Stimulated Release Devices
[0083] Monolithic devices have been prepared using polyelectrolyte
gels which swelled when, for example, an external electrical
stimulus was applied, causing a change in pH. The release could be
modulated, by the current, giving a pulsatile release profile.
[0084] 8. Hydrogels
[0085] Hydrogels find a use in a number of biomedical applications,
in addition to their use in drug matrices (e.g., soft contact
lenses, and various `soft` implants, etc.).
C. Methods of Using Controlled Release Isosorbide Dinitrate and
Hydralazine Hydrochloride Compositions
[0086] The present invention further provides a method of treating
a patient suffering from angina, ischaemic heart disease, arterial
hypertension and related disease conditions utilizing an isosorbide
dinitrate and hydralazine hydrochloride composition of the present
invention comprising the administration of a therapeutically
effective amount of a solid oral dosage form of isosorbide
dinitrate and hydralazine hydrochloride to provide a pulsed or
multi-modal or zero order delivery of the isosorbide dinitrate and
hydralazine hydrochloride. Advantages of the present invention
include reducing the dosing frequency required by conventional
multiple IR dosage regimes while still maintaining the benefits
derived from a pulsatile plasma profile or eliminating or
minimizing the "peak" to "trough" ratio. This reduced dosing
frequency is advantageous in terms of patient compliance to have a
formulation which may be administered at reduced frequency. The
reduction in dosage frequency made possible by utilizing the
present invention would contribute to reducing health care costs by
reducing the amount of time spent by health care workers on the
administration of drugs.
[0087] In the following examples, all percentages are weight by
weight unless otherwise stated. The term "purified water" as used
throughout the Examples refers to water that has been purified by
passing it through a water filtration system. It is to be
understood that the examples are for illustrative purposes only,
and should not be interpreted as restricting the spirit and breadth
of the invention, as defined by the scope of the claims that
follow.
Example 1
Multiparticulate Modified Release Composition Containing Isosorbide
Dinitrate and Hydralazine Hydrochloride
[0088] A multiparticulate modified release composition according to
the present invention comprising an immediate release component and
a modified release component containing isosorbide dinitrate and
hydralazine hydrochloride is prepared as follows.
(a) Immediate Release Component.
[0089] A powder blend of isosorbide dinitrate or hydralazine
hydrochloride is prepared according to any of the formulations
given in Table 1.
A binder solution is prepared according to any of the formulations
given in Table 2. A protective coating solution is prepared
according to any of the formulations given in Table 3.
[0090] The powder blend is then layered onto a suitable substrate
(e.g. sugar spheres or microcrystalline cellulose pellets) using a
suitable binder solution to a level of approximately 400% solids
weight gain using, for example, a Vector Granurex GX-40 (Vector
Corporation, IA) rotary granulator apparatus to form the IR
particles of the immediate release component. After the powder
layering process is complete, the protective coating solution is
coated onto the immediate release beads to a level of approximately
3% protective compound based on the mass of immediate release beads
to be coated. A glidant powder blend consisting of talc, silicon
dioxide or a combination of the two is simultaneously applied
either separately or by suspension in the coating solution to
reduce sticking and static. Examples of the final compositions of
the immediate release beads are shown in Table 4.
TABLE-US-00001 TABLE 1 Powder blend compositions Amount Amount
Amount Ingredient (mg/g) (mg/g) (mg/g) Diluted isosorbide dinitrate
-- -- 980 (40:60 mannitol/lactose) Hydralazine hydrochloride 980
800 -- Talc 10 10 10 Silicon dioxide 10 10 10 Fumaric acid -- 180
--
TABLE-US-00002 TABLE 2 Binder solution compositions Ingredient
Amount (mg/g) Amount (mg/g) Isopropanol 900 883.4 Povidone 100 100
Edetate disodium -- 16.6
TABLE-US-00003 TABLE 3 Protective coating solution compositions
Ingredient Amount (mg/g) Isopropanol 937.5 Basic butylated
methacrylate copolymers 62.5
TABLE-US-00004 TABLE 4 Immediate release component compositions
Amount Amount Amount Amount Ingredient (mg/g) (mg/g) (mg/g) (mg/g)
Povidone 56.6 56.6 56.6 56.6 Edetate disodium -- 9.4 -- 9.4
Isosorbide dinitrate -- -- 273.7 270.0 Mannitol/Lactose -- -- 410.5
405.0 Hydralazine hydrochloride 684.2 551.0 -- -- Talc 21.1 21.0
21.1 21.0 Silicon dioxide 21.1 21.0 21.1 21.0 Fumaric acid -- 124.0
-- -- Basic butylated methacrylate 28.3 28.3 28.3 28.3 copolymers
Sugar spheres (30/35 mesh) 188.7 188.7 188.7 188.7
(b) Modified Release Components
[0091] Isosorbide dinitrate and hydralazine hydrochloride
containing delayed release particles are prepared by coating
immediate release particles prepared according to Example 1(a)
above with a modified release coating solution as detailed in Table
5. Talc is simultaneously applied during coating as a glidant and
anti-static agent. The immediate release particles are coated to
varying levels up to approximately 30% polymer weight gain using,
for example, a rotary granulator or fluid bed apparatus. Example
compositions of the modified release components representing 20%
polymer weight gain are shown in Table 6.
TABLE-US-00005 TABLE 5 Modified release component coating solutions
Ingredient Amount (mg/g) Isopropanol 856 Water 24 Methacrylic acid
copolymers 100 Triethyl citrate 20
TABLE-US-00006 TABLE 6 Modified release component compositions
Amount Amount Amount Amount Ingredient (mg/g) (mg/g) (mg/g) (mg/g)
Povidone 39.3 39.3 39.3 39.3 Edetate, disodium -- 6.5 -- 6.5
Isosorbide dinitrate -- -- 190.0 187.5 Mannitol/Lactose -- -- 285.1
281.2 Hydralazine hydrochloride 475.1 382.6 -- -- Talc 153.6 153.5
153.6 153.5 Silicon dioxide 14.7 14.6 14.7 14.6 Fumaric acid --
86.1 -- -- Basic butylated methacrylate 19.7 19.7 19.7 19.7
copolymers Sugar spheres (30/35 mesh) 131.0 131.0 131.0 131.0
Methacrylic acid copolymers 138.9 138.9 138.9 138.9 Triethyl
Citrate, USP 27.8 27.8 27.8 27.8
(c) Encapsulation of Immediate and Delayed Release Particles.
[0092] The immediate and delayed release particles prepared
according to Example 1(a) and (b) above are blended and
encapsulated in size 0 hard gelatin capsules to an overall dosage
strength of 60/112.5 mg of isosorbide dinitrate and hydralazine
hydrochloride, respectively, using, for example, a Bosch GKF 400S
encapsulation apparatus. The overall dosage strength of 60/112.5 mg
isosorbide dinitrate and hydralazine hydrochloride, is made up of
40/75 mg from the immediate release component and 20/37.5 mg from
the modified release component.
[0093] It will be apparent to those skilled in the art that various
modifications and variations can be made in the methods and
compositions of the present inventions without departing from the
spirit or scope of the invention. Thus, it is intended that the
present invention cover the modification and variations of the
invention provided they come within the scope of the appended
claims and their equivalents.
* * * * *