U.S. patent application number 14/415114 was filed with the patent office on 2015-07-23 for gastro-retentive drug delivery system.
This patent application is currently assigned to APeT Holding B.V.. The applicant listed for this patent is APeT Holding B.V.. Invention is credited to Willem Blom, Lekhram Changoer, Anko Cornelus Eissens, Henderik Willem Frijlink, Hendrik Jan Cornelis Meijerink, Marinella Regina Visser.
Application Number | 20150202158 14/415114 |
Document ID | / |
Family ID | 44800307 |
Filed Date | 2015-07-23 |
United States Patent
Application |
20150202158 |
Kind Code |
A1 |
Meijerink; Hendrik Jan Cornelis ;
et al. |
July 23, 2015 |
GASTRO-RETENTIVE DRUG DELIVERY SYSTEM
Abstract
The invention relates to floating drug delivery systems(FDDS)
that provide solutions to the particular problems often encountered
with floating drug delivery systems described in the art. On such
generally recognized problem is the vulnerability of the systems,
especially damage to the gas-filled compartment making it
accessible to water so as to impair its buoyancy, ultimately
resulting in insufficient gastric residence time. The invention, in
an aspect, provides a self-repairing FDDS that maintains its
floating capacity after damaging. The floating drug delivery
systems of the invention, furthermore,allow for incorporation of
high loads of active ingredients. The floating drug delivery
systems can be designed in such a way that release of active
ingredient from the system occurs entirely independent from the pH
of the fluid surrounding the system. Furthermore, the procedure of
manufacturing the floating drug delivery system of the invention is
simple and straightforward, and therefore economically
attractive.
Inventors: |
Meijerink; Hendrik Jan
Cornelis; (Wespelaar, BE) ; Changoer; Lekhram;
(Ijsselstein, NL) ; Blom; Willem; (Berkel en
Rodenrijs, NL) ; Visser; Marinella Regina;
(Groningen, NL) ; Frijlink; Henderik Willem;
(Groningen, NL) ; Eissens; Anko Cornelus;
(Groningen, NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
APeT Holding B.V. |
Ridderkerk, |
|
NL |
|
|
Assignee: |
APeT Holding B.V.
Ridderkerk,
NL
|
Family ID: |
44800307 |
Appl. No.: |
14/415114 |
Filed: |
July 15, 2013 |
PCT Filed: |
July 15, 2013 |
PCT NO: |
PCT/NL2013/050538 |
371 Date: |
January 15, 2015 |
Current U.S.
Class: |
424/452 ;
424/490; 424/494; 424/497 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/1676 20130101; A61K 9/4808 20130101; A61K 9/1652 20130101;
A61P 25/00 20180101; A61K 9/1641 20130101; A61K 31/198 20130101;
A61K 9/4891 20130101; A61K 9/0065 20130101; G01N 33/6893 20130101;
A61K 31/455 20130101; A61K 9/1635 20130101; A61P 25/14 20180101;
Y10T 436/143333 20150115 |
International
Class: |
A61K 9/16 20060101
A61K009/16; A61K 31/455 20060101 A61K031/455; A61K 31/198 20060101
A61K031/198; A61K 9/00 20060101 A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 16, 2012 |
NL |
PCT/NL2012/050511 |
Claims
1-18. (canceled)
19. A floating drug delivery system (FDDS), comprising a particle
having a hollow, gas-filled core bordered by a wall of at least one
aqueous soluble, erodible, disintegrating or degradable polymer,
the wall being surrounded by a coating comprising at least one
active ingredient and a water-swellable polymer that swells upon
contact with water.
20. The floating drug delivery system according to claim 19,
wherein the particle is a capsule.
21. The floating drug delivery system according to claim 19,
wherein the active ingredient is not nicotinamide.
22. The floating drug delivery system according to claim 19,
wherein the system maintains its release profile and floating
properties when mechanically damaged or ruptured
23. The floating drug delivery system according to claim 19,
wherein the water-swellable polymer comprises hypromellose.
24. The floating drug delivery system according to claim 19,
wherein the coating comprises a water-swellable polymer other than
hypromellose.
25. The floating drug delivery system according to claim 19,
wherein the water-swellable polymer is selected from the group
consisting of hydrophilic cellulose derivatives, such as HPMC, HPC,
MC, HEC, CMC, sodium-CMC); PVP; PVA; carboxyvinyl polymer
(carbomer); poly(ethyleneoxide) (polyox WSR), alginates, pectins,
guar gum, vinylpyrrolidone-vinyl acetate compolymer; dextrans;
carrageenan; gellan; hyaluronic acid; pullulan; scleroglucan;
xanthan; and xyloglucan.
26. The floating drug delivery system according to claim 19,
comprising one or more coating layers comprising a combination of
HPMC and starch as coating material.
27. The floating drug delivery system according to claim 26, having
HPMC and starch in a ratio within the range of 8:1-1:1.
28. The floating drug delivery system according to claim 26,
comprising at least two active ingredient containing coating layers
having distinct ratios of hypromellose and starch, the outer layer
typically comprising a larger amount of hypromellose, relative to
starch, than the inner layer.
29. The floating drug delivery system according to claim 19,
capable of remaining in the stomach for at least 6 hours and/or of
releasing active ingredient to the stomach and proximal small
intestine for at least 6 hours.
30. The floating drug delivery system according to claim 19,
wherein the coating is selected from the group consisting of
coatings resistant to gastric juice, release-controlling coatings,
and mixtures thereof.
31. The floating drug delivery system according to claim 30,
wherein the release-controlling coating comprises: (a) a swellable,
poorly water-soluble or water-insoluble polymer; (b) one or more
enteric polymeric material(s); (c) a mixture of at least two
release controlling polymers; (d) a mixture of an enteric polymer,
and a release controlling polymer.
32. The floating drug delivery system according to claim 19, having
a density less than 0.95 g/cm.sup.3.
33. The floating drug delivery system according to claim 19, having
a density less than 0.8 g/cm.sup.3.
34. A floating drug delivery system (FDDS), comprising a particle
having a hollow, gas-filled core bordered by a wall of at least one
aqueous soluble, erodible, disintegrating or degradable polymer,
the wall being surrounded by a coating comprising at least one
active ingredient.
35. A method for providing a floating drug delivery system
according to claim 34, comprising: (a) providing a gas-filled
particle made of at least one aqueous soluble, erodible,
disintegrating or degradable polymer; (b) providing a coating
dispersion comprising an active ingredient, a polymer, optionally
additive(s), in a volatile solvent; (c) applying at least one layer
of dispersion on the surface of particle; and (d) allowing the
evaporation of the volatile solvent such that a layer comprising
the active ingredient is formed at the surface of the particle.
36. The method according to claim 35, wherein the particle is a
capsule.
Description
FIELD OF THE INVENTION
[0001] The invention relates to the fields of pharmacy and
medicine. Among others, it relates to oral gastro-retentive drug
delivery systems, in particular floating drug delivery systems, and
the uses thereof in therapy.
BACKGROUND OF THE INVENTION
[0002] Oral administration of drugs is the most preferable way of
drug delivery due to the simple and comfortable use and flexibility
regarding dose strength and type of formulation. These factors may
increase patient compliance. More than 50% of commercial drugs
available in the market use oral administration for the delivery.
During the last five decades, numerous oral delivery systems have
been developed to act as a drug reservoir from which the active
substance is released over an extended period of time and at
controlled rate of release. However, there is evidence that in vivo
drug release of solid oral controlled released dosage form is
unpredictable despite its excellent in vitro release profile
(Welling, PG 1993). Moreover, drug absorption profiles are often
unsatisfactory in relation to the desired plasma profile and highly
variable among individuals. One of the reasons for the
unpredictable drug release, which causes variation in drug
absorption among volunteers and patients, is associated with the
transit time of the dosage form in the gastrointestinal tract
(GIT). Gastric residence time (GRT) appears to be a major cause of
overall transit time variability. First of all, the release of a
drug from the delivery system may vary with the location of the
drug in the GI-tract. If, for example, the drug release is pH
dependent, significant differences in the release rate in the
stomach and in the small intestine may exist. Secondly, the
absorption of a drug may occur only in a limited part of the
GI-tract. Once this part of the GI-tract is passed by the drug
dosage form, drug release may occur in a reduced absorption or no
absorption at all any longer. Since many drugs are absorbed in the
proximal site of small intestine, GRT is an important variable that
affects to a large extent oral drug absorption of controlled
release dosage form. For drugs that are absorbed only in a limited
part of the GI-tract, the limited residence time in the stomach and
the upper small intestine, results in low oral bioavailability.
[0003] One of the options to reduce the variability in drug release
and drug absorption and to increase the bioavailability of drugs
from orally administered drug delivery systems, especially
controlled release drug delivery systems, is to prolong the
residence time of the dosage from in the stomach. Delivery systems
that are intended for this purpose are often described as
gastro-retentive dosage forms. Gastro-retentive dosage forms are
delivery systems that will provide the system to be able to control
the gastric residence time or gastric transit time of the dosage
form to achieve a prolonged and predictable drug delivery profile
in the upper part of the GI-tract. Controlling the residence time
of drug delivery system in the stomach will control the overall
gastrointestinal transit time since GRT appears to be the major
causes of overall transit time variability, thereby resulting in an
improved bioavailability of the drug.
[0004] The main objective in the development of gastro-retentive
dosage forms is to overcome the clearance of gastric content that
under normal circumstances occurs within 1-2 hours in the fasted
stated by the housekeeping wave. Over the past three decades, the
pursuit and exploration of devices designed to be retained in the
upper part of the gastrointestinal (GI) tract has advanced
consistently in terms of technology and diversity. Gastric
retention will provide advantages such as the delivery of drugs
with a limited absorption window to those parts of the intestinal
tract where absorption (with a slow release profile). Also, a
longer residence time in the stomach could be advantageous for
local action in the stomach or the upper part of the small
intestine, for example treatment of peptic ulcer disease, or
eradication of Helicobacter pylori. Furthermore, improved
bioavailability is expected for drugs that are absorbed
preferentially from the upper part of the GI-tract such as the
duodenum. These drugs can be delivered ideally by slow release from
the stomach. Many drugs categorised as once-a-day delivery have
been demonstrated to have suboptimal absorption due to dependence
on the gastro-intestinal transit time of the dosage form, making
traditional extended release development challenging. Therefore, a
system designed for longer gastric retention will extend the time
during which drug absorption can occur in for example the upper
small intestine.
[0005] Various approaches have been followed to encourage gastric
retention of an oral dosage form. Floating systems have low bulk
density so that they can float on the gastric juice in the stomach.
For reviews on floating drug delivery systems, see Singh et al.
(2000; J. Contr. Rel. 63, 235-259) and Arora et al. (2005, AAPS
PharmSciTech; 6(3) E372-E390) and references cited therein.
Briefly, gastro-retentive systems can be based on the following
concepts: [0006] A) buoyant (floating) systems: these are systems
that have a density lower that that of the gastric fluids so that
they remain floating in the stomach. These systems can be
subdivided in: [0007] A1) low-density systems have a density lower
than that of the gastric fluid so they are buoyant; [0008] A2)
hydrodynamically balanced systems (HBS)--incorporated buoyant
materials enable the device to float; [0009] A3) effervescent
systems--gas-generating materials such as carbonates are
incorporated. These materials react with gastric acid and produce
carbon dioxide (gas), which allows them to float; The system
contains means, such as a coating, to keep the gas for some time in
the delivery system. [0010] A4) raft systems incorporate gels such
as alginate or HPMC gels--these have a carbonate component and,
upon reaction with gastric acid, bubbles form in the gel, enabling
floating; [0011] B) bioadhesive or mucoadhesive systems--these
systems permit a given drug delivery system to be incorporated with
bio/mucoadhesive agents, enabling the device to adhere to the
stomach (or other GI) walls, thus resisting gastric emptying.
[0012] C) systems that have a size or will expand in the stomach to
a size that is too large to pass the pyloric sphincter.
[0013] A number of major drug companies have focused efforts on the
design of gastric retention technologies. For instance, Alza
Corporation has developed a gastro-retentive platform for the
OROS.RTM. system, which showed prolonged gastric residence time in
a dog model as the product remained in the canine stomach at 12
hours post dose and was frequently present at 24 hours. In humans,
in the fasted state, the average gastric residence time for the
same system was 33 minutes. DepoMed, Inc. has developed technology
that consists of a swellable tablet. After ingestion of the tablet,
it swells and achieves sufficient size to resist gastric emptying,
while simultaneously providing controlled release of the drug. Two
of the products that DepoMed is developing include Metformin GR.TM.
and Ciprofloxacin GR.TM.. Pfizer Pharmaceuticals has patents for
gastric retention technology that uses extendable arms. Merck &
Co., Inc., has patents describing technologies using various
unfolding shapes to encourage gastric retention. Madopar.RTM. is an
HBS floating system containing 200 mg levodopa and 50 mg
benserazide. The formulation consists of a capsule designed to
float on the stomach contents. Following dissolution of the gelatin
shell, a matrix body is formed consisting of the active drug and
other substances.
[0014] A major disadvantage of many of the systems described above
is that they require special production technologies and/or
specific machinery. For example, tabletting machines able to
produce multi-layer tablets are necessary to produce swellable
multi-layer tablets. A floating system patented by Eisa Co. Ltd.
had the problem of incorporating the drug (see Singh et al. (2000;
J. Contr. Rel. 63, 235-259). The production of systems using
effervescence has limitations regarding the use of aqueous liquids
and the systems containing effervescence couples require special
(e.g. moisture protecting) packaging. The production of systems
with a special shape requires special compaction or moulding tools.
Many systems may suffer from limitations in dose strength;
swellable systems may for example require large fractions of
polymers in the system. Many of the excipients (such as the
polymers used) may not have been tested as safe excipients yet or
they may be rather expensive. Furthermore, many of the systems may
have a high cost of production because of the combination of
specially adapted machinery and expensive excipients they require.
Finally, many systems suffer from the fact that they are rather
fragile and their gastro-retentive performance may be seriously
compromised in case of damage of the dosage form, e.g. a fissure or
crack in a coating layer, an edge broken from a tablet or
inactivation of the effervescent system by moisture.
[0015] The above developments highlight the continuous need and
industrial interest for developing new gastric retention
formulations that can readily be developed, tested and
manufactured. In view of this ongoing need, the present inventors
set out to provide an alternative gastro-retentive dosage form.
They aimed in particular at the development of an economically
attractive oral drug delivery system allowing for the controlled
and prolonged gastric residence of solid drug dosage forms, which
would readily be accepted by registration authorities and that was
able to provide controlled release of the drug(s) over periods
between 1.5 and 24 hour after administration. One further goal was
to provide a floating system that is simple and relatively cheap to
manufacture. Yet a further goal was to provide a system that is
physically robust and/or does not loose its gastro-retentive
properties upon minor damage.
SUMMARY OF THE INVENTION
[0016] It was surprisingly found that at least some of these goals
could be met by the provision of a floating drug delivery system
(FDDS), comprising a particle having a hollow, gas-filled core
bordered by a wall of at least one aqueous soluble, erodible,
disintegrating or degradable material, typically a polymer, said
wall being surrounded by a coating comprising at least one active
ingredient.
[0017] The present invention, in an aspect, provides a solution to
the particular problems encountered with many drugs that are
absorbed (only/mainly) in the proximal site of small intestine The
formulations facilitate absorption of active ingredient into the
systemic circulation from only a limited part of the (proximal)
intestinal tract for an extended period of time after
administration, by enhancing the gastro-rentention or gastric
residence time of the delivery system, while continuously releasing
active ingredient from the system.
[0018] Surprisingly, the present inventors established that, at
least in some cases, the use of oral long acting formulations of
the invention allows for effective and treatments, not only with
fewer dosages per day, but also with total daily dosages
significantly below those suggested in the art.
[0019] In a particularly preferred embodiment of the invention, the
floating drug delivery system (FDDS) comprises a coating containing
a polymer that swells upon contact with water. An FDDS according to
this embodiment has the advantage that it can maintain its buoyancy
even when (severely) damaged. The vulnerability of floating drug
delivery systems is a generally recognized problem. Damaging of the
drug delivery system, such as is often encountered during
production, transportation and, especially, during ingestion (e.g.
as a result of inadvertent chewing motions by the subject taking
the formulation), may easily make the gas-filled compartment
accessible to water so as to impair its buoyancy, ultimately
resulting in insufficient gastric residence time. A solution to
this problem is provided by the present invention, as will be
illustrated in the appended examples.
[0020] The floating drug delivery systems of the invention,
contrary to many floating dosage forms described in the art, allow
for incorporation of high loads of active ingredients, as will be
apparent from the examples.
[0021] It has also been established that, in accordance with the
invention, floating drug delivery systems can be developed wherein
release of active ingredient from the system occurs entirely
independent from the pH of the fluid surrounding the system.
[0022] Furthermore, in contrast to (multi)particulate floating
dosage forms, the procedure of manufacturing the floating drug
delivery system of the invention is simple and straightforward, and
therefore economically attractive, in particular when the particle
is filled with air.
[0023] These and other aspects of the invention and its preferred
embodiments will be described in more detail and exemplified in the
following sections.
DETAILED DESCRIPTION OF THE INVENTION
[0024] A first aspect of the invention concerns a floating drug
delivery system (FDDS), comprising a particle having a hollow,
gas-filled core bordered by a wall of at least one aqueous soluble,
erodible, disintegrating or degradable material, said wall being
surrounded by a coating comprising at least one active
ingredient.
[0025] A particularly preferred embodiment of the invention, a
floating drug delivery system (FDDS) is provided, comprising a
particle having a hollow, gas-filled core bordered by a wall of at
least one aqueous soluble, erodible, disintegrating or degradable
polymer, said wall being surrounded by a coating comprising at
least one active ingredient.
[0026] In one embodiment, the invention provides a FDDS comprising
a capsule having a hollow, gas-filled core bordered by a wall of at
least one aqueous soluble, erodible, disintegrating or degradable
polymer, said wall being surrounded by a coating comprising at
least one active ingredient.
[0027] It will be understood that essentially any type of active
ingredient can be incorporated in the coating. The expression
`active ingredient` refers to any compound having biological
activity, or being capable of being converted to such compound
(e.g. a pro-drug). In embodiments of this inventions the term
`active ingredient` is synonymous for and interchangeable with the
terms `pharmacologically active ingredient`, `pharmaceutically
active ingredient`, `therapeutically acceptable ingredient`,
`drug`, etc. In embodiments of this invention, the term `active
ingredient` also encompasses micronutrients, neutraceuticals, food
supplements, probiotics, prebiotics, etc.
[0028] Examples of (pharmacologically/pharmaceutically) active
ingredients that can benefit from using gastro-retentive drug
delivery devices include drugs acting locally in the stomach; drugs
that are primarily absorbed in the stomach or, in particular, in
the upper intestinal tract; drugs that are poorly soluble at an
alkaline pH; drugs with a narrow window of absorption; drugs
absorbed rapidly from the GI tract; drugs that are absorbed only or
mainly in the proximal site of small intestine and/or drugs that
degrade in the lower intestinal tract or colon. It may be a
material selected from the group consisting of AIDS adjunct agents,
alcohol abuse preparations, Alzheimer's disease management agents,
amyotrophic lateral sclerosis therapeutic agents, analgesics,
anesthetics, antacids, antiarythmics, antibiotics, anticonvulsants,
antidepressants, antidiabetic agents, antiemetics, antidotes,
antifibrosis therapeutic agents, antifungals, antihistamines,
antihypertensives, anti-infective agents, antimicrobials,
antineoplastics, antipsychotics, antiparkinsonian agents,
antirheumatic agents, appetite stimulants, appetite suppressants,
biological response modifiers, biologicals, blood modifiers, bone
metabolism regulators, cardioprotective agents, cardiovascular
agents, central nervous system stimulants, cholinesterase
inhibitors, contraceptives, cystic fibrosis management agents,
deodorants, diagnostics, dietary supplements, diuretics, dopamine
receptor agonists, endometriosis management agents, enzymes,
erectile dysfunction therapeutics, fatty acids, gastrointestinal
agents, Gaucher's disease management agents, gout preparations,
homeopathic remedy, hormones, hypercalcemia management agents,
hypnotics, hypocalcemia management agents, immunomodulators,
immunosuppressives, ion exchange resins, levocarnitine deficiency
management agents, mast cell stabilizers, migraine preparations,
motion sickness products, multiple sclerosis management agents,
muscle relaxants, narcotic detoxification agents, narcotics,
nucleoside analogs, non-steroidal anti-inflammatory drugs, obesity
management agents, osteoporosis preparations, oxytocins,
parasympatholytics, parasympathomimetics, phosphate binders,
porphyria agents, psychotherapeutic agents, radio-opaque agents,
psychotropics, sclerosing agents, sedatives, sickle cell anemia
management agents, smoking cessation aids, steroids, stimulants,
sympatholytics, sympathomimetics, Tourette's syndrome agents,
tremor preparations, urinary tract agents, vaginal preparations,
vasodilators, vertigo agents, weight loss agents, Wilson's disease
management agents, and mixtures thereof.
[0029] Examples of active ingredients that may be particularly
suitable for incorporation in the FDDS of the invention include
acetaminophen, acetylsalicylic acid, acyclovir, amoxycillin,
ampicillin, aspirin, atenolol, baclofen, benserazide, bifosfonaten
(alendronate), captopril, carbidopa, chlordiazepoxide,
chlordiazepoxide, chlorpheniramine, cinnarizine, ciprofloxacin,
cisapride, diazepam, diclofenac, diltiazem, florouracil,
furosemide, gabapentin, ganciclovir, G-CSF, glipizide,
griseofulvin, iboprufen, ijzer zouten, indomathacin, isosorbide,
ketoprofen, levodopa, melatonin, metformine, minocyclin,
misoprostol, nicardipine, nimodipine, p-aminobenzoic acid,
pentoxyfillin, piretanide, p-nitroaniline, prednisolone,
propranlol, quinidine gluconate, riboflavin,
riboflavin-5'-Phosphate, sotalol, terfenadine, tetracycline,
theophylline, tranilast, urodeoxycholic acid, ursodeoxycholic acid,
verapamil and vitamin E.
[0030] In an embodiment of the invention, the active ingredient is
levodopa, or a salt ester, derivative, hydrate and/or solvate
thereof. Levodopa is the INN name for L-3,4-dihydrophenylalanine.
In an embodiment of the invention the active ingredient is a
dopamine precursor or a catecholamine precursor. In an embodiment
of the invention the active ingredient is a dopamine agonist. In an
embodiment of the invention the active ingredient is a combination
of levodopa and carbidopa.
[0031] In an embodiment of the invention, the active ingredient is
nicotinamide. Nicotinamide (IUPAC name pyridine-3-carboxamide),
also known as niacinamide and nicotinic acid amide, is the amide of
nicotinic acid (vitamin B3/niacin). It will be understood by the
skilled reader that nicotinamide, as well as other compounds used
in the present invention, may be capable of forming salts,
complexes, hydrates and solvates, and that the use of such forms in
the defined treatments is contemplated herein.
[0032] In a preferred embodiment, the active ingredient is not
nicotinamide. In a preferred embodiment the active ingredient is
not nicotinamide or a salt, a complex, a hydrate or a solvate
thereof. An embodiment of the invention concerns a floating drug
delivery system (FDDS), comprising a particle, preferably a
capsule, having a hollow, gas-filled core bordered by a wall of at
least one aqueous soluble, erodible, disintegrating or degradable
polymer, said wall being surrounded by a coating comprising at
least one active ingredient, wherein said coating comprises a
polymer that swells upon contact with water, with the exception of
a floating drug delivery system (FDDS), comprising a particle
having a hollow, gas-filled core bordered by a wall of at least one
aqueous soluble, erodible, disintegrating or degradable polymer,
said wall being surrounded by a coating comprising
nicotinamide.
[0033] In a preferred embodiment a floating drug delivery system is
provided that, upon administration to a subject to be treated, is
capable of remaining in the stomach for a period extending over at
least 2, at least 3, at least 4, at least 5 or at least 6 hours,
typically in the fasted state. In an embodiment the FDDS is capable
of remaining in the stomach for a period extending over at least 12
or at least 24 hours, typically in the fasted state. Furthermore,
in a preferred embodiment of the invention an FDDS is provided
that, upon administration to a subject to be treated, is capable of
releasing active ingredient to the GIT (stomach and proximal small
intestine) for a period extending over at least 2, at least 3, at
least 4, at least 5 or at least 6 hours, typically in the fasted
state. In an embodiment the FDDS is capable of releasing active
ingredient to the GIT for a period extending over at least 12 or at
least 24 hours, typically in the fasted state. Furthermore, in a
preferred embodiment of the invention an FDDS is provided that, in
a standard in vitro test in a so called USP dissolution apparatus,
is capable of releasing active ingredient from the delivery system
in a so called slow release profile. Such a release profile is
preferably characterized by a release of less than 45% of the total
active ingredient content after 1 hour and/or the release of more
than 30% and less than 75% after 3 hours and/or the release of less
than 80% after 6 hours. In an alternative embodiment the release
profile is characterized by the release of less than 35% of the
total active ingredient content after 1 hour and/or the release of
more than 30% and less than 75% after 5 hours and/or the release of
more than 80% of the total active ingredient content after 10
hours. In an alternative embodiment the release profile is
characterized by the release of less than 25% of the total active
ingredient content after 1 hour and/or the release of more than 30%
and less than 75% after 12 hours and/or the release of more than
80% of the total active ingredient content after 24 hours.
[0034] Unless specified otherwise in this document, in vitro
testing of the FDDS system is carried out in a so called USP
dissolution apparatus II. With the dissolution medium (500 to 900
ml) at a temperature of 37.degree. C. and a rotational speed of the
paddle of 50 tot 75 RPM. For investigating the release profile or
floating capacity of the gastro-retentive systems, simulated
gastric fluid of the following composition is used: sodium lauryl
sulphate 2.5 g; sodium chloride 2.0 g; 0.01-0.05 N hydrochloric
acid in water 1000 ml. Active ingredient concentrations in the
dissolution medium can be determined by any suitable analytical
method, like ultraviolet absorption or HPLC analysis.
[0035] In a preferred embodiment of the invention an FDDS is
provided, which remains buoyant on the gastric fluid upon
administration, typically to achieve the afore-defined goals.
Usually the buoyancy is characterized by the floating time (h)
and/or buoyancy AUC (mg h). In a preferred embodiment of the
invention a floating delivery system is provided having a floating
time of at least 2, at least 3, at least 4, at least 5 or at least
6 hours when tested in vitro in the USP dissolution apparatus II.
In an embodiment an FDDS is provided having a floating time of at
least 12 or at least 24 hours when tested in vitro in the USP
dissolution apparatus II.
[0036] Preferably, in the FDDS of the invention, active ingredient
is present in a coating that encompasses or surrounds a solid
particle made of at least one aqueous soluble, erodible,
disintegrating or degradable polymer (e.g. by coating onto the
surface of the particle), said particle having a hollow, gas-filled
core bordered by a wall of at least one degradable polymer. As will
be understood, the gas is a non-toxic gas. Air is the preferred
gas. Because of the gas-filled compartment, lacking any particulate
matter or matrix components, an FDDS provided herein having unique
floating capacity and therefore very good gastric retention
properties. Using an established in vitro gastric fluid simulation
system, a floating time of at least up to 24 hours was observed.
Thus, provided herein is gastric retention device capable of
remaining in the stomach for at least 6, preferably at least 9,
more preferably at least 12 hours. Also provided is the use of an
air-filled capsule, generally lacking any therapeutically active
ingredient, as a floating carrier for a drug in a gastro-retentive
drug formulation.
[0037] According to the invention, the active ingredient is present
in an outer layer or coating that controls not only the penetration
of liquid (e.g. gastric fluid) into the particle, but also the
release of active ingredient from the particle. Thus, in contrast
to floating systems known in the art comprising (sub)compartments
or chambers filled with air, such as floating microspheres, the
present invention is conceptually different in that the active
ingredient is present on the exterior of the gas filled
compartment, and essentially absent (at least upon manufacture)
from the inner core of a particle.
[0038] As will be explained below, the particle may be a
conventional gelatin or HPMC capsule known in the art, which is
easily provided with a coating comprising active ingredient. The
system can be produced using only excipients that are known to be
safe for human or animal use and that are accepted by regulatory
authorities.
[0039] Typically, the particle in the FDDS of the invention itself
will lack any therapeutically active ingredient and only contains
active ingredient in the external coating layer. However, it is
also encompassed that a small (e.g. up to about 50%, preferably up
to 35% or 30%, more preferably up to 20%, like 5, 10, 12, 15 or
17%) volume of the capsule or other type of hollow particle is
filled with active ingredient, or another active ingredient, as
long as the overall density of the capsule remains sufficiently low
to allow for floating. Therefore, also provided is the use of a
capsule of which only 50% or less, preferred is 35% or less even
more preferred 20% or less, of the volume is filled with active
ingredient or another active ingredient and the remaining volume is
gas-filled as floating carrier for a drug in a gastro-retentive
drug formulation. Only when the capsule erodes or disintegrates,
its content is released. This may for instance be advantageous for
applications wherein it is desirable to provide a final "burst"
dose of the drug at the end of the release period. For example, a
FDDS comprising the majority of active ingredient in the particle
coating and a minor fraction within the coated particle allows
achieving low yet sustained blood drug levels during the night,
followed by an increased drug level in the morning. This is
especially advantageous for the treatment of diseases wherein
symptoms are worse in the morning, such as rheumatoid arthritis
(RA) or asthma.
[0040] To protect the stomach lining to continued exposure of
certain active ingredients, an embodiment is envisaged wherein the
FDDS contains the active ingredient in microencapsulate form, which
microencapsulates are dispersed within the external coating layer
of the FDDS. The microencapsulate typically contains a core
comprising or consisting of active ingredient covered by a layer of
enteric polymer, designed to dissolve upon entry of the released
microcapsules from the stomach into the small intestine.
Alternatively the microencapsulate may simply comprise particles
containing active ingredient dispersed within an enteric polymer
matrix, designed to dissolve upon entry of the released
microencapsulate from the stomach into the small intestine.
[0041] The skilled person will be able to select the appropriate
materials to obtain a coating, and optionally a micorencapsulate
for incorporation in said coating, yielding the desired
characteristics with respect to liquid penetration and the release
of the active ingredient in accordance with the afore described
embodiments.
[0042] In a preferred embodiment of the invention, an FDDS as
defined herein is provided, comprising a coating layer containing
active ingredient in an amount of at least 40 wt. %, at least 50
wt. %, at least 60 wt. %, at least 70 wt. %, at least 75 wt. %, or
at least 80 wt. %, based on the total weight of said coating layer,
of active ingredient.
[0043] The active ingredient may be present in two or more layers
of the coating, each layer having a distinct composition. It is
also possible to provide the particle with a "subcoating" and/or
"topcoating" to achieve a desired GRT and/or release profile. A
single coating layer comprising active ingredient may be preferable
in some embodiments for reasons of simplicity. However, in other
preferred embodiments several layers of coatings may be applied,
typically having distinct compositions and active ingredient
amounts. As will be shown in the examples, the use of two or three
coating layers having distinct release profiles allows for the
design of formulations capable of near constant active ingredient
release over periods of up to 12 hours. In one such embodiment an
FDDS is provided comprising three coating layers, wherein the inner
layer comprises 50-90 wt %, 60-87 wt % or 70-85 wt % of active
ingredient, based on the total weight of the inner coating layer;
the middle layer comprises 30-70 wt %, 40-60 wt % or 45-55 wt % of
active ingredient, based on the total weight of the middle coating
layer; and the outer layer comprises less than 10 wt %, less than 5
wt % or less than 1 wt % of active ingredient based on the total
weight of the outer coating. In another embodiment an FDDS is
provided comprising two coating layers, wherein the inner layer
comprises 50-90 wt %, 60-87 wt % or 70-85 wt % of active
ingredient, based on the total weight of the inner coating layer;
and the outer layer comprises less than 10 wt %, less than 5 wt %
or less than 1 wt % of active ingredient based on the total weight
of the outer coating layer.
[0044] The coating materials of the one or more coating layers may
be selected from the group consisting of coating materials
resistant to gastric juice, release-controlling polymers, and
mixtures thereof. Release-controlling polymers are well known in
the art of drug formulations for controlled (e.g. sustained)
release, and include swellable polymers, or polymers that are
poorly water-soluble or water-insoluble. Exemplary release
controlling polymers are hydrophilic cellulose derivatives (such as
HPMC, HPC, MC, HEC, CMC, sodium-CMC), PVP, PVA, Carboxyvinyl
polymer (Carbomer), Poly(ethyleneoxide) (Polyox WSR), alginates,
pectins, guar gum, vinylpyrrolidone-vinyl acetate copolymer,
dextrans, carrageenan, gellan, hyaluronic acid, pullulan,
scleroglucan, xanthan, xyloglucan, chitosan, poly(hydroxyethyl
methacrylate), ammoniomethacrylate copolymers (such as Eudragit RL
or Eudragit RS), Poly(ethylacrylate-methylmetacrylate) (Eudragit
NE), and Ethylcellulose. The coating may comprise a mixture of at
least two release controlling polymers. For instance, a combination
of HPMC and Eudragit RL was found to be very useful. Eudragit RL PO
is a polymer for controlled release drug formulation. Due to the
insolubility in the acid fluids of the stomach it is able to give a
release of active ingredients over the desired period of time.
[0045] In another preferred embodiment, the invention provides a
floating drug delivery system comprising a particle having a
hollow, gas-filled core bordered by a wall, as defined herein, and
comprising one or more coating layers comprising a combination of
HPMC and starch as coating material, typically in a ratio within
the range of 8:1-1:1, preferably 6:1-2:1, more preferably 5:1-3:1,
most preferably about 4:1. The use of hypromellose was found to
favourably delay active ingredient release.
[0046] In a particularly preferred embodiment of the present
invention, said starch is pregelatinized starch.
[0047] In another preferred embodiment, the invention provides a
floating drug delivery system comprising a particle having a
hollow, gas-filled core bordered by a wall comprising one or more
coating layers comprising a combination of HPMC and pregelatinized
starch as coating material, typically in a ratio within the range
of 1:1-1:8, preferably 1:1-1:6, more preferably 1:1-1:5, most
preferably 1:1-1:4. As will be evident from the appending examples,
the combination of hypromellose and pregelatinized starch is very
advantageous in that it allows for accurate programming of active
ingredient release, depending on the choice and nature of the
active ingredient.
[0048] In preferred embodiments of the invention, an FDDS is
provided comprising at least two active ingredient containing
coating layers, e.g. as described here above, having distinct
ratios of hypromellose and starch, the outer layer typically
comprising a larger amount of hypromellose, relative to starch,
than the inner layer.
[0049] In a particularly preferred embodiment of the present
invention, said starch is pregelatinized starch.
[0050] In another preferred embodiments of the invention, an FDDS
is provided comprising an active ingredient containing inner
coating layer, e.g. as described here above, as well as an outer
coating layer that does not contain active ingredient. The use of
an outer coating layer allows for accurate programming of active
ingredient release, as will be illustrated in the appended
examples. In an embodiment, the inner and outer coating layers
comprise hypromellose and pregelatinized starch. The inner and
outer layer may comprise hypromellose and pregelatinized starch in
the same (relative) amounts. In an embodiment the outer layer
typically comprises a larger amount of hypromellose, relative to
pregelatinized starch, than the inner layer.
[0051] Furthermore, it has been established that coating layers
comprising hypromellose or other water-swellable polymers
maintained their favourable release profile and floating properties
when mechanically damaged or even ruptured, as will be illustrated
in the examples here below.
[0052] Finally, it was established that the FDDS produced with
these compositions was physically strong and robust, with crushing
strengths far over 100 N. Hence, in an embodiment of the invention,
an FDDS as defined herein is provided having a crushing-strength of
at least 100 N, more preferably of at least 150 N.
[0053] Hence, a preferred embodiment of the invention concerns the
FDDS as defined herein, and its use, wherein a polymer is used that
swells upon contact with water, so as to render the FDDS
`self-repairing`. Most preferably said water-swellable polymer is
hypromellose. In an embodiment of the invention, said
water-swellable polymer is not hypromellose.
[0054] A particularly preferred embodiment of the invention
concerns a floating drug delivery system (FDDS), comprising a
particle, preferably a capsule, having a hollow, gas-filled core
bordered by a wall of at least one aqueous soluble, erodible,
disintegrating or degradable polymer, said wall being surrounded by
a coating comprising at least one active ingredient, wherein said
coating comprises a polymer that swells upon contact with
water.
[0055] Another preferred embodiment of the invention concerns a
floating drug delivery system (FDDS), comprising a particle,
preferably a capsule, having a hollow, gas-filled core bordered by
a wall of at least one aqueous soluble, erodible, disintegrating or
degradable polymer, said wall being surrounded by a coating
comprising at least one active ingredient, wherein said coating
comprises hypromellose or another water-swellable polymer.
[0056] Another preferred embodiment of the invention concerns a
floating drug delivery system (FDDS), comprising a particle,
preferably a capsule, having a hollow, gas-filled core bordered by
a wall of at least one aqueous soluble, erodible, disintegrating or
degradable polymer, said wall being surrounded by a coating
comprising at least one active ingredient, wherein said floating
drug delivery system maintains its release profile and floating
properties when mechanically damaged or ruptured
[0057] Another preferred embodiment of the invention concerns a
floating drug delivery system (FDDS), comprising a particle,
preferably a capsule, having a hollow, gas-filled core bordered by
a wall of at least one aqueous soluble, erodible, disintegrating or
degradable polymer, said wall being surrounded by a coating
comprising at least one active ingredient, wherein a polymer is
used that swells upon contact with water, so as to render the FDDS
self-repairing.
[0058] Another preferred embodiment of the invention concerns a
floating drug delivery system (FDDS), comprising a particle,
preferably a capsule, having a hollow, gas-filled core bordered by
a wall of at least one aqueous soluble, erodible, disintegrating or
degradable polymer, said wall being surrounded by a coating
comprising at least one active ingredient, wherein said coating
comprises a water-swellable polymer other than hypromellose.
[0059] Another preferred embodiment of the invention concerns a
floating drug delivery system (FDDS), comprising a particle,
preferably a capsule, having a hollow, gas-filled core bordered by
a wall of at least one aqueous soluble, erodible, disintegrating or
degradable polymer, said wall being surrounded by a coating
comprising at least one active ingredient, wherein said coating
comprises a water-swellable polymer is not hypromellose.
[0060] Typically, by "water swellable polymer" is meant a polymer
that does not readily dissolve in water (or does not dissolve in
water at all) but interacts with water to cause the polymer to
increase in volume. Water swellable polymers useful in the
preparation of the FDDS of this invention include polymers that are
non-toxic and that swell in a dimensionally unrestricted manner
upon imbibition of water and hence of gastric fluid. Examples of
polymers meeting this description are: cellulose polymers and their
derivatives including, but not limited to, hydroxymethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, and carboxymethylcellulose;
polysaccharides and their derivatives; polyalkylene oxides;
polyethylene glycols; chitosan; poly(vinyl alcohol); xanthan gum;
maleic anhydride copolymers; poly(vinyl pyrrolidone); starch, in
particular pregelatinized starch, and starch-based polymers;
carbomer; maltodextrins; amylomaltodextrins, dextrans,
poly(2-ethyl-2-oxazoline); poly(ethyleneimine); polyurethane
hydrogels; and crosslinked polyacrylic acids and their derivatives.
Further examples are copolymers of the polymers listed above,
including block copolymers and graft polymers. Specific examples of
copolymers are PLURONIC.RTM. and TECTONICS.RTM., which are
polyethylene oxide-polypropylene oxide block copolymers available
commercially. Further examples are hydrolyzed starch
polyacrylonitrile graft copolymers.
[0061] In a particularly preferred embodiment of the invention
concerns a floating drug delivery system (FDDS), comprising a
particle, preferably a capsule, having a hollow, gas-filled core
bordered by a wall of at least one aqueous soluble, erodible,
disintegrating or degradable polymer, said wall being surrounded by
a coating comprising at least one active ingredient, wherein said
coating comprises a polymer selected from the group consisting of
hydrophilic cellulose derivatives, such as HPMC, HPC, MC, HEC, CMC,
sodium-CMC); PVP; PVA; carboxyvinyl polymer (carbomer);
poly(ethyleneoxide) (polyox WSR), alginates, pectins, guar gum,
vinylpyrrolidone-vinyl acetate compolymer; dextrans; carrageenan;
gellan; hyaluronic acid; pullulan; scleroglucan; xanthan;
xyloglucan.
[0062] In a preferred embodiment of the invention, an FDDS as
defined herein is provided, wherein at least 50 wt. %, at least 60
wt. %, at least 70 wt. %, at least 75 wt. %, at least 80 wt. %, at
least 85 wt. %, at least 90 wt. % or at least 95 wt. % of the
coating excipients, i.e. of the materials contained in the coating
other than the active ingredient(s), is a water-swellable polymer
as defined in the foregoing.
[0063] The FDDS coating may also comprise one or more enteric
polymer coating materials. The term "enteric polymer" is a term of
the art referring to a polymer which is preferentially soluble in
the less acid environment of the intestine relative to the more
acid environment of the stomach. Useful enteric polymers for
practising the present invention include cellulose acetate
phthalate, cellulose acetate succinate, methylcellulose phthalate,
ethylhydroxycellulose phthalate, polyvinylacetatephthalate,
polyvinylbutyrate acetate, vinyl acetate-maleic anhydride
copolymer, styrene-maleic mono-ester copolymer, methacrylic acid
methylmethacrylate copolymer, methyl acrylate-methacrylic acid
copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer,
and combinations thereof.
[0064] In a specific aspect, the invention provides a delivery
system comprising a particle having a hollow, gas-filled core
bordered by a wall of at least one aqueous soluble, erodible,
disintegrating or degradable material, typically a polymer, said
wall being surrounded by a coating comprising at least one enteric
polymer and active ingredient, preferably wherein the enteric
polymer is a pharmaceutically acceptable methacrylic acid
methylmethacrylate copolymer, such as a polymer sold under the
trade name Eudragit.TM., including polymers from the Eudragit RL or
Eudragit RS series. Again, mixtures of different types of coating
polymers may be used. In one embodiment, the coating comprises a
mixture of an enteric polymer, such as Eudragit RL, and a release
controlling polymer, preferably a water-sweallable release
controlling polymer. As is exemplified below, a combination of HPMC
and Eudragit RL, for instance in relative weight ratio's of between
1:2 and 2:1, give very good results.
[0065] In addition to the coating polymer(s), a coating may
comprise one or more additives having a beneficial or otherwise
desired effect on a property of the coating. Useful additives
include a plasticizer, a stabiliser, a pH adjuster, a GI motility
adjuster, a viscosity adjuster, a diagnostic agent, an imaging
agent, an expansion agent, a surfactant, and mixtures thereof.
[0066] In one embodiment, the coating comprises a plasticizer. The
group of plasticizers contains, but is not limited to, materials
such as PEG6000 (also known as Macrogol 6000), triethyl citrate,
diethyl citrate, diethyl phthalate, dibutyl phthalate, tributyl
citrate, and triacetin. The quantity of plasticiser included will
be apparent to those skilled in the art. Typically the coating may
include around 2-15 wt. % plasticiser based on the total dry weight
of the coating. The enteric coating may also include an anti-tack
agent such as talc, silica or glyceryl monostearate.
[0067] As will be understood, floating dosage forms rely on their
ability to float on gastric fluid. Gastric fluid has a density
close to that of water, which is 1.004 g/ml. Therefore, for the
system to remain afloat, the overall density of the system must be
less than 1 g/ml. In one embodiment, a drug delivery system
according to the invention has a density of less than 0.95
g/cm.sup.3. Lower densities, such as less than 0.9 g/cm.sup.3 ,
more preferably less than 0.8 g/cm.sup.3 are of course preferred.
In a specific aspect, the density is less than 0.7 g/cm.sup.3.
[0068] Of particular interest is the inclusion in the coating
comprising active ingredient of an effervescent (gas forming)
compound, i.e. an agent capable of generating CO.sub.2 in situ upon
contact with acid such as gastric fluid. This will provide the FDSS
of the invention with additional buoyancy. Effervescent compounds
are used already in the art of floating dosage forms and include
sodium bicarbonate, sodium carbonate, or sodium glycine carbonate.
However, the use of effervescent compounds has been limited
primarily to either (a) single layer systems wherein gas forming
material is mixed with the drug or (b) multiparticulate unit
systems comprising a conventional sustained release pill, coated
with a bilayer system consisting of an inner effervescent layer and
an outer layer of swellable membrane (see Bardonnet et al. J
Control Release 2006; 111(1-2)1-18).
[0069] The wall of the gas-filled particle is made of an aqueous
soluble, erodible, disintegrating and/or biodegradable material,
typically a polymer, such that the floating drug delivery system
leaves no trace behind in the body. Suitable polymers that are
aqueous soluble, erodible, disintegrating and/or biodegradable are
well known in the art, and include gelatine and hydroxypropyl
methylcellulose (HPMC).
[0070] The shape and size of the particle can vary. Of course, for
oral administration purposes it is preferred that the particle can
be swallowed. A preferred particle is a conventional gastric
erodible/soluble capsule, such as a gelatine capsule or a HPMC
capsule. Soft shells are also encompassed. The particle can be a
single or a multi-particulate capsule. In one embodiment, the
invention provides a FDDS comprising a capsule having a hollow,
gas-filled core bordered by a wall of at least one aqueous soluble,
erodible, disintegrating or degradable material, typically a
polymer, said wall being surrounded by a coating comprising at
least one active ingredient. In view of gastric retention time, it
is preferred that an oral gastro-retentive dosage form is as large
as possible (to minimize passage through the pylorus) yet
sufficiently small to be swallowed. Preferably, a FDDS provided
herein comprises an oblong shaped capsule having a length of at
least 10 mm, preferably at least 14 mm, more preferably at least 16
mm, most preferably at least 19 mm, and/or a diameter of at least 5
mm preferably at least 6 mm, more preferred at least 7, most
preferred at least 8 mm. Suitable capsules include those referred
to in the art as Type 5, 4, 3, 2, 2el, 1, 1el, 0, Oel, 00, 00el or
000 capsules. Alternatively, wide body capsules (BDCaps.RTM.) may
be used. These capsules are referred to in the art as E, D, C, B,
A, AA, AAel or AAA.
[0071] The FDDS as described herein provides an alternative
gastro-retentive dosage form that is simple and relatively cheap to
manufacture. A floating drug delivery system (FDDS) comprising
active ingredient can be prepared using a method comprising the
steps of (a) providing a gas-filled particle made of at least one
aqueous soluble, erodible, disintegrating or degradable polymer and
(b) providing a coating solution or a coating dispersion comprising
active ingredient, a coating polymer, optionally additives, in a
volatile solvent. Then, at least one layer of coating dispersion is
applied onto the surface of particle, typically by spraying or dip
coating. Application may be direct onto the aqueous soluble,
erodible, disintegrating or degradable material, typically a
polymer, making up the wall of the particle. Alternatively, the
wall may first be provided with a sub-coating, on which the coating
comprising active ingredient is applied. Upon the evaporation of
the volatile solvent, a solid coating serving as "drug release
layer" is obtained. Furthermore the active ingredient-containing
layer may be covered by a top-coating that improve the appearance
of the capsule (e.g. giving it a colour) or contain taste-masking
components. Step (a) preferably entails the manufacture of a
conventional air-filled capsule according to well-established
methods. The capsule can be a two-part conventional capsule as well
as a single unit air filled capsule. Step (b) in itself is also
standard practice in the art of controlled release dosage forms.
The skilled person will be able to choose the type(s) and relative
amount(s) of the components to obtain a coating solution or a
coating dispersion that provides the particle with a drug coating
having the desired release properties. A suitable volatile solvent
is an alcohol, such as ethanol or isopropanol. Alternatively
aqueous solutions or suspensions could be used. The solution or
dispersion may contain between about 10 and 600 gram of dry matter
per liter solvent, such as between 50 and 150 gram per liter. The
concentrations and relative amount of active ingredient in the
coating dispersion may depend on the dosage amount to be achieved.
In general, the coating dispersion will contain between about 1 and
50 wt % of active ingredient based on the total dry weight of the
dispersion. It is important that the coating dispersion is
sufficiently homogeneous to obtain a good coating uniformity. This
can be achieved by thorough mixing. When dip coating is applied
even higher amounts of dry matter could be added to the volatile
solvent. An aspect of the invention relates to the above-described
methods for providing a floating drug delivery system (FDDS).
[0072] As will be illustrated in the examples here below, the FDDS
of the present invention can be loaded with relatively high amounts
of active ingredient, i.e. as compared to other types of floating
drug delivery systems. Depending on the target subject and/or
dosage regimen, suitable dosage forms of the FDDS can be developed.
In one embodiment, the FDDS comprises a particle (capsule) having a
hollow, gas-filled core bordered by a wall of at least one aqueous
soluble, erodible, disintegrating or degradable polymer, said wall
being surrounded by a coating comprising 10 mg to 10 gram of active
ingredient. Preferably, the coating comprises 20 to 8000 mg of
active ingredient, more preferably 25 to 5000, such as 20-1000,
50-500 or 1000-2500. Preferred examples of the FDDS of the
invention contain active ingredient in a total amount of 100, 150
mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg or 600 mg.
[0073] A floating drug delivery system as provided herein is
advantageously used for the treatment or prophylaxis of a disease,
for example in a method comprising administering to a patient in
need thereof a composition comprising a floating drug delivery
system (FDDS) according to the invention, wherein the at least one
active ingredient is capable of treating or preventing the disease.
The FDDS is preferably formulated for oral administration. In one
embodiment, a method of the invention comprises administering to a
patient in need of such treatment or prophylaxis a composition
comprising an oral floating drug delivery system (FDDS), the system
comprising a controlled release coating comprising at least one
active ingredient against the disease coated onto the surface of a
solid particle, said particle having a hollow, gas-filled core
bordered by a wall of at least one aqueous soluble, erodible,
disintegrating or degradable material, typically a polymer. It will
be understood that an FDDS of the invention, as with other floating
systems, works optimal if the stomach of the subject receiving the
FDDS is at least partially filled with gastric fluid. Therefore, it
is preferred that the subject is a non-fasted subject. In case the
subject is a fasted subjects, the method comprises administering to
the subject an oral floating drug delivery system (FDDS) together
with a sufficient amount of fluid, e.g. an amount of water of at
least 100 ml, preferably at least 200 ml.
[0074] In one aspect, the invention provides a method for treating
or preventing a disease which is located in the stomach or upper
intestinal tract, comprising administering to a patient in need
thereof a composition comprising a floating drug delivery system
(FDDS) according to the invention, and wherein the active
ingredient is useful in the local treatment of the disease. In
another aspect, the invention provides a method for treating or
preventing a disease, comprising oral systemic drug administration,
and wherein the active ingredient is absorbed into the systemic
circulation from only a limited part of the intestinal tract.
[0075] A FDDS of the invention is particularly useful for
delivering a therapeutic agent to the stomach or upper intestinal
tract of a patient and/or for enhancing the gastric retention of an
agent in the stomach of a patient, the method comprising oral
administration to the patient of a composition comprising a
floating drug delivery system (FDDS), wherein a coating comprising
the therapeutic agent is coated onto the surface of a solid
particle, preferably a capsule, said particle having a hollow,
gas-filled core bordered by a wall of at least one aqueous soluble,
erodible, disintegrating or degradable material, typically a
polymer.
[0076] Also encompassed is a method of enhancing the
gastrointestinal absorption of a drug which is absorbed into the
systemic circulation over only a limited part of the small
intestine of a patient, the method comprising oral administration
to the patient of the drug being incorporated in a FDSS as provided
herein.
[0077] As will be understood by those skilled in the art, the
principal features of this invention can be employed in the various
aspects and embodiments without departing from the scope of the
invention. More, in particular, it is contemplated that any feature
discussed in this specification can be implemented with respect to
any of the methods, compositions and uses of the invention, and
vice versa.
[0078] Furthermore, for a proper understanding of this invention
and its various embodiments it should be understood that in this
document and the appending claims, the verb "to comprise" is used
in its non-limiting sense to mean that items following the word are
included, but items not specifically mentioned are not excluded. In
addition, reference to an element by the indefinite article "a" or
"an" does not exclude the possibility that more than one of the
element is present, unless the context clearly requires that there
be one and only one of the elements. The indefinite article "a" or
"an" thus usually means "at least one".
[0079] The following examples describe various new and useful
embodiments of the present invention. It will be understood that
particular embodiments described herein are shown by way of
illustration and not as limitations of the invention. Those skilled
in the art will recognize, or be able to ascertain using no more
than routine experimentation, numerous equivalents to the specific
procedures described herein. Such equivalents are considered to be
within the scope of this invention and are covered by the
claims.
EXAMPLE 1
[0080] A typical example of a gastro-retentive system can be
obtained by coating of an empty gelatine capsule with coating
comprising at least one pharmacologically active ingredient.
[0081] In a specific embodiment the gelatine capsule is coated with
a suspension containing: [0082] drug (e.g. nicotinamide): 1 to 95%
of the solids in the suspension; [0083] polymers and release
controlling agents: 5 to 99% of the solids in the suspension.
[0084] The amount of drug that will be sprayed onto the capsule is
determined by the desired dose of the drug and the concentration of
the drug in the coating. The composition of the drug containing
coating layer is determined by the desired release profile. Typical
polymers like Hypromellosum 4000 mPas., viscosity 2% m/V or
Eudragit RL PO can be used whereas plasticizers such as
Polyethylenglycolum 6000 or dibutyl phthalate can be used. Other
excipients that can be used in the coating suspension are magnesium
stearate, talc or mannitol. The coating suspension is applied on
the gelatine capsules in equipment such as fluidized beds or
perforated pan-coaters.
[0085] A second example of a gastro-retentive system can be
obtained by the incorporation of gas-forming materials in a tablet
that contains a hydrophilic gel forming polymer.
[0086] In a specific embodiment such a tablet would contain:
TABLE-US-00001 drug 0.5 to 90%; HPMC 4000 10 to 80%; sodium
carbonate 5 to 20%; Sodium stearyl fumarate 0.5 to 5%.
[0087] Furthermore excipients such as fillers, binders, glidants,
lubricants and others known in the art of tablet formulation can be
added to the formulation. The tablets can be made according to well
known tablet production technologies such as direct compaction, dry
granulation or wet granulation techniques. Tablet compaction can be
performed using tablet machines widely known in the pharmaceutical
industry.
EXAMPLE 2
Dissolution of Nicotinamide from FDDS
Materials
[0088] HPMC (Hypromellosum 4000 mPas., viscosity 2% m/V) was
obtained from Bufa BV, Uitgeest, The Netherlands. Macrogol 6000
(Polyethylenglycolum 6000) was obtained from Fagron, The
Netherlands. Eudragit RL PO (Pharma Polymere, Rohm GmbH) was
obtained from Chemische Fabric, Kirschenallee, Darmstadt, Germany.
Nicotinamide Ph.Eur.quality was used.
Methods
[0089] A number of different coating dispersions (also referred
herein as "suspensions") were prepared (see Table 1). The required
amount of HPMC was weighted to a beaker and then mixed with Ethanol
(100 ml). Subsequently, the nicotinamide was added in the amounts
indicated below. In parallel, in another beaker Macrogol 6000 was
prepared by melting at a temperature not higher than 80.degree. C.,
after melting, ethanol (50 ml) was added and subsequently the
required amount of Eudragit RL PO was added. The cooled solution
was mixed with the contents of the first beaker to provide a
coating dispersion.
TABLE-US-00002 TABLE 1 composition of the different coating
suspensions. Ingredient Coating 1 Coating 2 Coating 3 HPMC 4.0 g
4.0 g 5.0 g Eudragit RL PO 3.5 g 3.5 g 3.5 g Macrogol 6000 1.0 g
1.0 g 1.0 g nicotinamide 5.0 1.0 5.0 ethanol 150 ml 150 ml 150
ml
[0090] Hard gelatine capsules (No.3) were coated with the different
coating dispersions using an appropriate spray nozzle according to
standard procedures. Briefly, the coating dispersion was sprayed
onto the surface of the capsules rotating in a small container
under a heated air stream until the required amount of drug-polymer
mixture as determined by weight analysis was sprayed on the
capsules.
[0091] Dissolution test were performed in a beaker with 500 ml of
0.1 M HCl at pH=1.03-1.09 at a temperature of 34-38.degree. C.
while stirring at 150 rpm using a magnetic stirrer.
[0092] Samples (2.5 ml) were taken every 30 minutes up to 7 hours
with a syringe. The samples were analysed at 280 nm for the content
of active ingredients using a spectrophotometer.
Results
[0093] Four capsules were coated with coating dispersion 1, and two
of them were subjected to the dissolution test in a beaker with 500
ml of 0.1N HCl. After six hours, more than 95% of active substance
was released, showing that drug release was complete after 6 hours.
The capsule was still floating on the 0.1N HCl after 24 hours.
[0094] Coating dispersion 2 was used to coat four capsules, and two
of them were subjected to the dissolution test. After six hours,
more than 90% of active substance was released. The capsule was
still floating on the 0.1N HCl after 24 hours.
[0095] Coating dispersion 3 was used to coat another four capsules
and two of them were subjected to the dissolution test. After six
hours, less than 50% of active substance was released. The higher
quantity of HPMC in coating 3 leads to a slower release of active
substance. Moreover the release was incomplete. This shows that, by
varying the polymer content of the coating composition, the rate of
drug release from the floating particle can be altered. The capsule
was still floating on the 0.1N HCl after 24 hours.
EXAMPLE 3
Development of a 300 mg and a 600 mg Nicotinamide Gradient FDDS
Background
[0096] The concept of an FDDS comprising several layers of distinct
composition and distinct amounts of nicotinamide was tested. Also
the concept of an FDDs comprising an outer coating layer comprising
no nicotinamide was tested.
[0097] The aim of the experiment was to optimize the formulation,
especially to prevent an initial release burst and to prolong the
period of constant nicotinamide release, preferably over the entire
residence time of the FDDS in the stomach. This involved testing of
formulations containing outer coatings containing a high percentage
of hypromellose and outer coatings containing no nicotinamide as
well as formulations containing an inner layer with a high
percentage of starch.
Materials & Methods
[0098] Nicotinamide was purchased from Sigma-Aldrich, hypromellose
400 mPas from Bufa, Starch 1500 from Colorcon and magnesium
stearate from Genfarma by. In all experiments demineralized water
was used. The release profiles were determined in 0,01N HCl. For
the preparation of coating suspensions acetone was used.
[0099] Hypromellose is a swelling agent that is used to delay the
release of nicotinamide. The hydrophilic drug is released via
diffusion. Starch and magnesium stearate show a faster release of
nicotinamide. This influence of the various excipients has been
investigated
[0100] To prepare the floating delivery system, a suspension
containing the excipients and the drug were sprayed on empty hollow
capsules. This was done using a spray-coat system. The different
substances are dissolved in water and acetone. The suspension
should be slightly viscous to prevent sedimentation and blockage in
the system. The ratio of acetone and distilled water depends on the
amount of hypromellose. At a low concentration of hypromellose
relatively more water is used so that the suspension has the
desired viscosity. The substances are first suspended and/or
dissolved in acetone prior to adding water. This prevents formation
of lumps in the slurry. The suspension is sprayed through a nozzle
(1 mm) together with air, so that small droplets are introduced
into the spraying sphere. The spraying sphere is heated from the
outside so that the acetone evaporates quickly and the substances
are coated on the capsules. Capsule sizes 3, 4 and 5 (Spruyt
Hillen) were used in various experiments. It was decided that
capsule size 4 was used which were `locked` by pressing the halfs
together so as to somewhat reduce the size.
[0101] The coatings consisted of different formulations with
different concentrations of nicotinamide, hypromellose, magnesium
stearate and starch, as will be described here below.
[0102] The produced capsules were tested for their floating
behaviour and release profile in a dissolution bath (Prolabo)
filled with 1 liter 0,01N HCl, 37.+-.1.degree. C., at 50 rpm. The
0,01N HCl was prepared by degassing 6 liter of demineralized water
and adding 8 ml 25% HCl. The release profiled were determined for
at least 12 hours by UV absorbance measurements at 280 nm (cuvet
1cm) (Ultrospec III, Pharmacia LKB). The floating behaviour was
followed by visual inspection. All experiments were performed in
2-, 3- or 5-fold.
[0103] The final formulation for a 300 mg gradient FDDS comprises 3
layers. The first layer surrounding the capsule has a concentration
of 80% nicotinamide (200 mg active). The second layer 50% (100 mg
active), and the third layer 0% (90 mg coating material). The
composition is shown in Table 2.
TABLE-US-00003 TABLE 2 composition of 300 mg nicotinamide FDDS.
Component 80% 50% 0% Nicotinamide 79% 49% -- Hypromellose 16% 40%
78% Starch 1500 4% 10% 20% Magnesium stearate 1% 1% 2% Amount of
active 200 mg 100 mg --
[0104] The final formulation for the 600 mg gradient FDDS comprises
2 layers. The inner layer consists of 80% nicotinamide. The layer
comprises 750 mg of the coating material. Around it is a 0% coating
of 150 mg. A SEM image was made of a cross-section of the FDDS in
which both layers could clearly be distinguished. The composition
of this FDDS is shown in Table 3.
TABLE-US-00004 TABLE 3 composition of 600 mg nictoinamide FDDS.
Component 80% 0% Nicotinamide 79% -- Hypromellose 16% 78% Starch
1500 4% 20% Magnesium stearate 1% 2% Amount of active 600 mg --
Results
[0105] FIGS. 1 and 2 show the release profiles of the 300 mg FDDS
and 600 mg FDDS respectively. A satisfactory release rate is
accomplished nearly over the entire 12 hour period. The results
show that the release profiles of the 300 en 600 mg FDDS's are
comparable.
[0106] The floating behaviour of both the FDDS's was also tested in
milk, simulating an environment containing substantial amounts of
fat. The FDDS's staid afloat for more than 12 hours.
Discussion/Conclusion
[0107] The 300 and 600 mg nicotinamide gradient FDDS's are capable
of staying afloat for at least 12 hours and of releasing
nicotinamide at a substantially constant rate for almost the entire
12 hour period.
[0108] To achieve this near constant release the FDDS's were
designed to comprise different layers of coating. For example, the
300 mg FDDS contained an inner layer with 200 mg nicotinamide (80%
based on the total weight of the layer), a middle layer with 100 mg
nicotinamide (50% based on the total weight of the layer) and an
outer layer that did not contain nicotinamide. The 600 mg FDDS
contained an inner layer with 600 mg nicotinamide (80% based on the
total weight of the layer) and an outer layer that did not contain
nicotinamide.
[0109] The use of distinct layers allowed for the regulation of the
overall release profile, to achieve near constant release rates of
periods of up to 12 hours.
EXAMPLE 4
Effects of Rupture of FDDS on Floating Capability and Release
Profile
Background
[0110] The present inventors decided to also investigate the
effects of mechanical damage to the FDDS. It was envisaged that
damaging of the formulation could easily arise when treating young
children as they might, for instance, `accidentally` chew or crush
the FDDS before swallowing. The floating behaviour and release
profiles of ruptured capsules were therefore tested and compared to
the floating behaviour and release profiles of intact FDDS's.
Materials & Methods
[0111] The FDDS's used for this experiment were of the multi-layer
gradient type. They were prepared and tested using the protocols
described in example 3. The composition is shown in table 4.
TABLE-US-00005 TABLE 4 composition of FDDS for rupturing experiment
80% 50% 0% Hypromellose 76% 19% 78% Starch 1500 4% 10% 20%
Magnesium stearate 1% 1% 2% Nicotinamide 79% 50% -- Each FDDS
contained 45 mg 0% coating.
[0112] The FDDS's proved to be strong and difficult to damage. The
FDDS's were placed in a bench vice that was tightened until the
wall of the FDDS began to rupture. The crushing strength was over
200 N for all products.
[0113] The floating behaviour as well as the release profile was
determined of both the damaged and undamaged the FDDS's.
Results
[0114] All FDDS's, ruptured and undamaged, staid afloat in the
testing liquid. After 18 hours remains were still afloat in the
dissolution beakers.
[0115] The release profiles of the FDDS's are shown in FIG. 3. As
can be seen in said figure, the release profiles of capsule 1 and 2
(undamaged FDDS's) did not differ significantly from that of
capsules 3 and 4 (ruptured FDDS's). During the first 4 hours, the
release profiles are identical. After 4 hours a minor difference
becomes apparent in that the release rate of the ruptured FDDS is
slightly higher than that of the non-damaged FDDS's. This
difference is however is never more than 8%.
Conclusion/Discussion
[0116] The FDDS of the invention is capable of staying afloat even
after mechanical damage and rupture. The damage hardly affects the
nicotinamide release profile. Possibly, because of the swelling of
the hypromellose upon contact with water, cracks in the wall are
effectively closed restoring the integrity of the FDDS.
EXAMPLE 5
In Vivo Release of Nicotinamide in Healthy Human Volunteers Using
FDDS
[0117] Healthy adults, 4 women and 4 men, were recruited as
volunteers in a trial to investigate the pharmacokinetic profile of
the nicotinamide FDDS of the invention. The trial was performed
with 300 and 600 mg FDDS formulations as described in example
3.
[0118] During the trial blood was sampled at pre-determined
intervals. Samples (Li-heparin) were collected and frozen for
storage. In addition urine was collected (24 h). The entire
protocol was as described in table 5.
TABLE-US-00006 TABLE 5 Protocol for determining PK profile of
Nicotinamide FDDS Start of trial 7:30 Arrival of subjects (empty
stomach) at test location. Canule for blood sampling is placed.
Blood sample T0 8:00 Subjects have breakfast (1-2 sandwiches) and
drinks (tea, fruit juice) 8:15 Subjects ingest nicotinamide FDDS
8:45 Blood sample T1 9:45 Blood sample T2 10:45 Blood sample T3
Subjects have drinks (tea, coffee, water and/or juice) 11:45 Blood
sample T4 12:30 Subjects have lunch (3-4 sandwiches) and drinks
((tea, coffee, water, and/orjuice) 13:00 Blood sample T5 16:00
Blood sample T6 Subjects have drinks (tea, coffee, water and/or
juice) After Subjects go home. Subjects continue to collect their
urine samples. 16:00 At home the subjects have dinner and drinks
(standard) and are told not to take alcohol containing drinks 7:30
Arrival of subjects (empty stomach) at test location and hand over
(next their urine samples. day) 8:00 Blood sample T7 End of
trial
[0119] The stored Li-heparin samples were analyzed using a standard
HPLC measurement. Measurements were performed with and without
protein removal from the plasma, as it appeared that the protein
removal negatively affected resolution of the analyte(s). These
problems, which could not be resolved instantaneously, did however
not prohibit the detection of the nicotinamide in the various
samples. For illustrative purposes, FIG. 4 is referred to, showing
the detection of nicotinamide in the plasma of one of the test
subjects. From this figure it can be inferred that the ingestion of
the FDDS caused a significant and persistent increase in the
subject's nicotinamide plasma level.
[0120] The overall results showed that the FDDS of the invention
was capable of maintaining an increased nicotinamide plasma levels
in vivo for a period of at least 8 hours after ingestion.
EXAMPLE 6
Preparation of Floating Drug Delivery System with Levodopa and/or
Carbidopa
Materials
[0121] Levodopa (Ph.Eur.quality), Carbidopa (Ph.Eur.5.8 quality)
and HPMC (Hypromellosum 4000 mPas., viscosity 2% m/V) were obtained
from Bufa BV, Uitgeest, The Netherlands). Macrogol 6000
(Polyethylenglycolum 6000) was obtained from Fagron, The
Netherlands. Eudragit RL PO (Pharma Polymere, Rohm GmbH) was
obtained from Chemische Fabric, Kirschenallee, Darmstadt,
Germany.
Methods
[0122] A number of different coating dispersions (also referred
herein as "suspensions") were prepared (see Table 6). The required
amount of HPMC was weighted to a beaker and then mixed with Ethanol
(100 ml). Subsequently, the active substances were added in the
amounts indicated below. In parallel, in another beaker Macrogol
6000 was prepared by melting at a temperature not higher than
80.degree. C., after melting, ethanol (50 ml) was added and
subsequently the required amount of Eudragit RL PO was added. The
cooled solution was mixed with the contents of the first beaker to
provide a coating dispersion.
TABLE-US-00007 TABLE 6 composition of the different coating
suspensions. Ingredient Coating 1 Coating 2 Coating 3 Coating 4
Coating 5 HPMC 4.0 g 4.0 g 5.0 g 5.0 g 4.0 g Eudragit RL 3.5 g 3.5
g 3.5 g 3.5 g 3.5 g PO Macrogol 1.0 g 1.0 g 1.0 g 1.5 g 1.0 g 6000
levodopa 6.0 g -- -- 7.0 g 7.0 g carbidopa -- 0.6 g 0.6 g 0.7 g 0.7
g Ethanol 150 ml 150 ml 150 ml 150 ml 150 ml
[0123] Hard gelatin capsules (No.3) were coated with the different
coating dispersions using an appropriate spray nozzle according to
standard procedures. Briefly, the coating dispersion was sprayed
onto the surface of the capsules rotating in a small container
under a heated air stream until the required amount of drug-polymer
mixture as determined by weight analysis was sprayed on the
capsules.
[0124] Dissolution test were performed in a beaker with 500 ml of
0.1 M HCl at pH=1.03-1.09 at a temperature of 34-38.degree. C.
while stirring at 150 rpm using a magnetic stirrer.
[0125] Samples (2.5 ml) were taken every 30 minutes up to 7 hours
with a syringe. The samples were analysed at 280 nm for the content
of active ingredients using a spectrophotometer. When the
combination capsules were analysed the absorption was assumed to be
caused by both the levodopa and the carbidopa in the same ratio as
they were present in the product. The assumption that both the drug
release and the contribution to the absorption were relative to the
presence of both components in the product can be justified by the
fact that the solubility of both materials is within the same order
of magnitude and by the fact that the specific absorption of the
materials differs less than 20%.
Results
[0126] All gelatin capsules were floating on the stirred 500 ml of
0.1N HCl up to a period of at least 24 hours from the onset of the
experiment.
[0127] Four capsules were coated with coating suspension 1, and two
of them were subjected to the dissolution test in a beaker with 500
ml of 0.1N HCl. The discussed capsule contained 87.4 mg levodopa
which was present in the polymer coating in a concentration of
41.4%. After six hours, 87.38 mg of active substance was released,
showing that drug release was complete after 6 hours. The capsule
was still floating on the 0.1N HCl after 24 hours.
[0128] FIG. 5 illustrates the dissolution profiles of a capsule
coated with levodopa in a coating comprising HPMC. Drug release is
expressed as percentage of the theoretical maximum. The figure
shows a representative levodopa release profile obtained with
coating suspension 1. The levodopa concentration in the simulated
gastric fluid gradually increases up to 5 hours, after which it
remained almost constant.
[0129] Coating suspension 2 was used to coat four capsules with
carbidopa, and two of them were subjected to the dissolution test.
The discussed capsule contained 11.67 mg carbidopa, constituting
6.59 wt % of the coating composition based on dry weight. After six
hours, 10.125 mg of active substance was released. FIG. 6
illustrates the dissolution profiles of a capsule coated with
carbidopa in a coating comprising different amounts of HPMC (see
Table 6). Drug release is expressed as percentage of the
theoretical maximum. FIG. 6 shows a representative carbidopa
release profile obtained with coating 2.
[0130] Coating suspension 3 was used to coat another four capsules
and two of them were subjected to the dissolution test. The
discussed capsule contained 10.50 mg carbidopa, constituting 5.94
wt % of the coating composition based on dry weight. After six
hours, 1.14 mg of active substance was released. FIG. 6 shows a
representative carbidopa release profile obtained with coating 3.
The higher quantity of HPMC in coating 3 leads to a slower release
of active substance. Moreover the release was incomplete. This
shows that, by varying the polymer content of the coating
composition, the rate of drug release from the floating particle
can be altered. Next, coating suspensions 4 and 5 comprising a
mixture of levodopa and carbidopa as active ingredients were
evaluated.
[0131] FIG. 7 illustrates the dissolution profiles of a capsule
coated with the combination of levodopa and carbidopa in a coating
comprising different amounts of HPMC (see Table 6). Drug release is
expressed as percentage of the theoretical maximum. The figure
shows that the release of levodopa and carbidopa from a capsule
coated with suspension 4 increases steadily in time. A capsule
contained 97.13 mg levodopa and 9.71 mg carbidopa which were
present in the coating at concentrations of 39.55% and 3.95%
respectively. In contrast, absorption of carbidopa and levodopa
combination in a market available normal dosage form like tablets
is rapid and virtually complete in 2-3 h. Extended- release tablets
absorption is gradual and continuous for 4-8 h, although the
majority of the dose is absorbed in 2 to 3 h. FIG. 7 also shows the
drug release from a capsule coated with suspension 5. The reduced
amount of HPMC in the coating resulted in a somewhat faster release
of the drug.
EXAMPLE 7
Development of a (+/-) 300 mg Levodopa FDDS
[0132] Four different floating drug delivery systems are produced
in accordance with this invention, containing Levodopa as the
active ingredient: [0133] Levodopa 1: size 4 capsule coated with a
first layer containing 79% levodopa (dry solids weight percentage)
and a combination of hypromellose, in a high hypromellose to starch
ratio and a second layer of said hypromellose starch combination
with 0% levodopa; [0134] Levodopa 2: size 4 capsule coated only
with a layer containing 79% levodopa (dry solids weight percentage)
and a combination of hypromellose, in a high hypromellose to starch
ratio; [0135] Levopdopa 3: size 4 capsule coated with a first layer
containing 79% levodopa (dry solids weight percentage) and a
combination of hypromellose, in a low hypromellose to starch ratio
and a second layer of said hypromellose starch combination with 0%
levodopa; and [0136] Levodopa 4: size 4 capsule coated only with a
layer containing 79% levodopa (dry solids weight percentage) and a
combination of hypromellose, in a low hypromellose to starch
ratio.
[0137] The precise compositions of the FDDSs and the suspensions
used for producing them is given in the following tables.
TABLE-US-00008 Levodopa 1 79% Ldopa coating 0% Ldopa coating FDDS
suspension FDDS suspension Levodopa 79% 8 g -- -- Hypromellose 16%
1.6 g 79% 3.2 g Pregelatinized starch 4% 0.4 g 20% 0.8 g Magnesium
stearate 1% 0.1 g 1% 0.1 g Aceton -- 90 ml -- 60 ml Water -- 15 ml
-- 7 ml Capsule size Size 4 `pressed to lock` Amount on FDDS corr.
to 330 mg of Ldopa 67 mg of coating
TABLE-US-00009 Levodopa 2 79% Ldopa coating 0% Ldopa coating FDDS
suspension FDDS suspension Levodopa 79% 8 g -- -- Hypromellose 16%
1.6 g -- -- Pregelatinized starch 4% 0.4 g -- -- Magnesium stearate
1% 0.1 g -- -- Aceton -- 90 ml -- -- Water -- 15 ml -- -- Capsule
size Size 4 `pressed to lock` Amount on FDDS corr. to 330 mg of
Ldopa 0 mg of coating
TABLE-US-00010 Levodopa 3 79% Ldopa coating 0% Ldopa coating FDDS
suspension FDDS suspension Levodopa 79% 8 g -- -- Hypromellose 4%
0.4 g -- -- Pregelatinized starch 16% 1.6 g -- -- Magnesium
stearate 1% 0.1 g -- -- Aceton -- 90 ml -- -- Water -- 15 ml -- --
Capsule size Size 4 `pressed to lock` Amount on FDDS corr. to 330
mg of Ldopa 0 mg of coating
TABLE-US-00011 Levodopa 4 79% Ldopa coating 0% Ldopa coating FDDS
suspension FDDS suspension Levodopa 79% 8 g -- -- Hypromellose 4%
0.4 g 78% 0.8 g Pregelatinized starch 16% 1.6 g 20% 0.2 g Magnesium
stearate 1% 0.1 g 2% 0.025 g Aceton -- 90 ml -- 25 ml Water -- 15
ml -- 2 ml Capsule size Size 4 `pressed to lock` Amount on FDDS
corr. to 300 mg of Ldopa 15 mg of coating
Floating Capacity and Release Profiles
[0138] Release profiles of Levodopa from all FDSSs was tested using
the USP dissolution system II (paddle method) (Prolabo) with 1 L of
0.01 N HCl as the dissolution medium (T=37.+-.1.degree. C.). All
FDDSs remained afloat in the dissolution bath during the entire
period of testing (12 hours).
[0139] In FIG. 8 the release curves of the levodopa 1-4 have been
plotted (percentage of the total Ldopa content dissolved vs. time).
The figure shows that the release profile of Ldopa can be
manipulated precisely. By changing the composition of the coating
polymers (in this case by changing the hypromellose to starch
ratio) the rate of release of Ldopa can be increased or decreased.
The formulations with a higher relative amount of hypromellose have
a lower rate of Ldopa release than the formulations with a higher
relative amount of starch. Besides the composition of the active
ingredient coating layer, the application of an additional layer of
coating (containing no Ldopa) can suitably be applied to lower the
rate of release of Ldopa, as can be derived clearly from the graphs
in FIG. 8 (i.e. by comparison of Levodopa 1 and levodopa 2 and by
comparison of levodopa 3 and levodopa 4).
Effect of Damage and Self-Repair Capacity
[0140] The FDDSs were tested for their ability to maintain their
floating capacity and the release profiles since many floating drug
delivery systems of the prior art are known to be very vulnerable
to damage resulting in impairment or total lack of their floating
capacity (and hence gastric retention). A common cause for damage
is inadvertant chewing movement by the subject taking the FDDS.
[0141] The FDDSs Levodopa 1-4 were damaged deliberately by
squeezing them in a bench-vice, until cracks/ruptures developed
visible to the naked eye. The damaged FDDSs were subjected to the
same tests as the undamaged FDDS' (as described above)
[0142] All damaged FDDSs remained afloat in the dissolution bath
during the entire period of testing (12 hours). The release
profiles of the damaged and undamaged FDDSs have been plotted in
FIG. 9 (9a: L-dopa 1, 9b: L-dopa 2; 9c: L-dopa 3; and 9d: L-dopa
4). As can be inferred from these figures, the effect of damaging
on the release profile is only marginal. At no time, the difference
in released levodopa between damaged and undamaged formulation
exceeded 8% and it was, in most cases below 5%.
[0143] To cause damage (cracking/rupture) visible to the naked eye,
a significant force had to be applied, which required the use of
the bench vice.
* * * * *