PULSATILE-RELEASE DOSAGE FORM
Field of the Invention
The present invention relates to pulsatile-release dosage forms wherein said dosage forms
provide pH-independent pulsatile-release of a drug after a predetermined lag time. It also relates to
processes for the preparation of said pulsatile-release dosage forms.
Background of the Invention
Several diseases show circadian rhythms in their pathophysiology. These include
cardiovascular diseases such as hypertension and acute myocardial infarction; neurological diseases
such as attention-deficit syndrome and Parkinson's syndrome; arthritis; asthma; cancer; peptic
ulcer; diabetes mellitus; and hypercholesterolemia.
Pulsatile-release dosage forms are highly promising and advantageous over conventional
immediate-release and extended-release dosage forms for the treatment of diseases that show a
predictable cyclic rhythm, because the time of drug delivery plays a key role in effective treatment
of these diseases. Pulsatile-release dosage forms deliver the drug at an appropriate time as per the
pathophysiological need of the disease, leading to an improved therapeutic efficacy and better
patient compliance. These dosage forms are designed according to the circadian rhythm of the
body so that the drug is released as a pulse after a predetermined lag time.
U.S. Publication No. 201 110189286 discloses a gastro-retentive pulsatile delivery system
for the sustained delivery .of valsartan, comprising an immediate-release (IR) component that
provides a first pulse of valsartan and a modified-release (MR) component that provides additional
pulse of valsartan, wherein valsartan is in a solubility enhanced form such that the pulsatile delivery
of valsartan occurs in a therapeutically effective and gastro-retentive manner.
U.S. Patent No. 6,663,888 discloses a histamine H2 antagonist pharmaceutical dosage form
providing a bi-modal pulsatile-release profile comprising: immediate-release (IR) beads
comprising an active-containing core particle and timed pulsatile-release (TPR) beads. The TPR
beads comprise an active-containing core particle and a pulse coating comprising a water-insoluble
polymer and an enteric polymer surrounding said core. The IR beads provide a therapeutically
effective amount of active to treat gastric acid secretions and TPR beads provide a delayed dose of
~ ~ active which provides a therapeutically effective amount of active to treat midnight GERD.
U.S. Patent No. 7,4 13,75 1 discloses a gastric retained dosage form comprising losartan and
a hydrophilic polymer such as polyethylene oxide, hydroxyethylcellulose, and
T n .-. piE%-!I 2.5 - 3 3 - ZQEG 17 145
2
hydroxypropylmethylcellulose. Losartan is administered from this dosage form for a period of at
least 5 hours and at least 40% wlw of the losartan is retained in the dosage form after 1 hour.
U.S. Publication No. 200510276853 discloses a chronotherapeutic pharmaceutical
formulation comprising a core of an active ingredient and a delayed-release compression coating of
a natural or synthetic gum applied onto the surface of the core.
Thereremains a need for a pulsatile-release dosage form in which the release of a drug is
delayed for as many hours as is desired, based on the pathophysiology of the disease. The present
inventors have now developed a novel pulsatile-release dosage form that provides release of the
drug after a predetermined lag time. The dosage form of the present invention is therefore
beneficial, as it avoids the unnecessary exposure of the target organ to the drug during those times
when therapeutic effect of the drug is not required. For instance, for the treatment of certain
disease conditions, said pulsatile-release dosage form may be administered prior to sleep so that the
drug is released well after the time of administration, for example, during morning hours. Such
administration results in effective treatment of early morning pathological symptoms in certain
disease conditions like hypertension and arthritis. Additionally, the pulsatile-release dosage form
of the present invention can be designed so as to target the drug-release at a particular site, such as
the lower portion of the gastro-intestinal tract.
Further, the release of the drug from the pulsatile-release dosage form of the present
invention is independent of the pH of the gastro-intestinal tract. The pulsatile-release dosage form
of the present invention is relatively simple, easy to manufacture, arid is functionally reproducible.
Summary of the Invention
The present invention relates to pulsatile-release dosage forms which provide pH
independent-release of a drug after a predetermined lag time. The pulsatile-release dosage forms
comprise: (i) a core comprising a drug and one or more pharmaceutically acceptable excipients;
and (ii) a coating layer over said core comprising a water-soluble polymer, a water-insoluble
polymer, a small molecular weight water-insoluble excipient, and one or more pharmaceutically
acceptable coating additives. Further, the present invention also includes processes for the
preparation of said pulsatile-release dosage forms.
Detailed Description of the Invention
A first aspect of the present invention provides a pulsatile-release dosage form comprising:
(a) a core comprising a drug and one or more pharmaceutically acceptable excipients; and
(b) a coating layer over said core comprising a water-soluble polymer, a water-insoluble
e m - k c - s b v L r ~r t_e e L t, ra'b po&B~,Ca3s~BDdd&cu~r7vrie@Bw ater-insoluble excipient, and one or more
3
pharmaceutically acceptable coating additives.
According to one embodiment of this aspect, there is provided a pulsatile-release dosage
form comprising:
(a) a core comprising a drug and one or more pharmaceutically acceptable excipients; and
(b) a coating layer over said core comprising hydroxypropyl methyl cellulose, ethyl
cellulose, magnesium stearate, and one or more pharmaceutically acceptable coating
additives.
According to another embodiment of this aspect, there is provided a pulsatile-release dosage
form comprising:
(a) a core comprising a drug and one or more pharmaceutically acceptable excipients; and
(b) a coating layer over said core comprising polyvinylpyrrolidone, ethyl cellulose,
magnesium stearate, and one or more pharmaceutically acceptable coating additives.
A second aspect of the present invention provides a pulsatile-release dosage form
comprising:
(a) a core comprising a drug and one or more pharmaceutically acceptable excipients; and
(b) a coating layer over said core comprising a water-soluble polymer, a water-insoluble
polymer, a small molecular weight water-insoluble excipient, and one or more
pharmaceutically acceptable coating additives,
wherein the core further comprises one or more rate-controlling polymers.
According to one embodiment of this aspect, there is provided a pulsatile-release dosage
form comprising:
(a) a core comprising a drug and one or more pharmaceutically acceptable excipients; and
(b) a coating layer over said core comprising hydroxypropyl methyl cellulose, ethyl
cellulose, magnesium stearate, and one or more pharmaceutically acceptable coating
additives,
wherein the core further comprises hydroxypropyl methyl cellulose.
A third aspect of the present invention provides a pulsatile-release dosage form comprising:
(a) a core comprising a drug and one or more pharmaceutically acceptable excipients; and
(b) a coating layer over said core comprising a water-soluble polymer, a water-insoluble
polymer, a small molecular weight water-insoluble excipient, and one or more
.r R 8 L - P +CL -S 2 S - r ; u - , - 2 8 B G 17 : 45
4
pharmaceutically acceptable coating additives,
wherein the core further comprises one or more gastro-retentive polymers.
, According to one embodiment of this aspect, there is provided a pulsatile-release dosage
form comprising:
(a) a core comprising a drug and one or more pharmaceutically acceptable excipients; and
(b) a coating layer over said core comprising hydroxypropyl methyl cellulose, ethyl
cellulose, rriagnesiurn stearate, and one or more pharmaceutically acceptable coating
additives,
wherein the core further comprises ~ollicoat@Pro tect and carbopol@.
A fourth aspect of the present invention provides a process for the preparation of a pulsatilerelease
dosage form, wherein the process comprises the steps of:
(a) blendinggranulating a drug and one or more pharmaceutically acceptable excipients;
(b) compressing the blends/granules of step (a) into a tablet core using appropriate
tooling;
(c) dissolving/dispersing a water-soluble polymer, a water-insoluble polymer, a small
molecular weight water-insoluble excipient, and one or more pharmaceutically
acceptable coating additives in a suitable solvent; and
(d) applying the coating composition of step (c) over the tablet core of step (b) to form the
pulsatile-release dosage form.
A fifth aspect of the present invention provides a process for the preparation of a pulsatilerelease
dosage form, wherein the process comprises the steps of:
(a) blending/granulating a drug, one or more rate-controlling polymers, and one or more
pharmaceutically acceptable excipients;
(b) compressing the blendslgranules of step (a) into a tablet. core using appropriate
tooling;
(c) dissolving/dispersing a water-soluble polymer, a water-insoluble polymer, a small
molecular weight water-insoluble excipient, and one or more pharmaceutically
acceptable coating additives in a suitable solvent; and
(d) applying the coating composition of step (c) over the tablet core of step (b) to form the
pulsatile-release dosage form.
A sixth aspect of the present invention.provides a process for the preparation of a pulsatilerelease
dosage form, wherein the process comprises the steps of:
(a) blendinglgranulating a drug, one or more gastro-retentive polymers, and one or more
pharmaceutically acceptable excipients;
(b) compressing the blendslgranules of step (a) into a tablet core using appropriate
tooling;
(c) dissolving/dispersing a water-soluble polymer, a water-insoluble polymcr, a small
molecular weight water-insoluble excipient, and one or more pharmaceutically
acceptable coating additives in a suitable solvent; and
(d) applying the coating composition of step (c) over the tablet core of step (b) to form the
pulsatile-release dosage form.
A seventh aspect of the present invention provides a process for the preparation of a
pulsatile-release dosage form, wherein the process comprises the steps of:
(a) blendinglgranulating a drug and one or more pharmaceutically acceptable excipients;
(b) filling the blendslgranules of step (a) into a suitable sized capsule to form a capsule
core;
(c) dissolving/dispersing a water-soluble polymer, a water-insoluble polymer, a small
molecular weight water-insoluble excipient, and one or more pharmaceutically
acceptable coating additives in a suitable solvent; and
(d) applying the coating composition of step (c) over the capsule core of step (b) to form
the pulsatile-release dosage form.
An eighth aspect of the present invention provides a process for the preparation of a
pulsatile-release dosage form, wherein the process comprises the steps of:
(a) blendinglgranulating a drug, one or more rate-controlling polymers, and one or more
pharmaceutically acceptable excipients;
(b) filling the blendslgranules of step (a) into a suitable sized capsule to form a capsule
core;
(c) dissolving/dispersing a water-soluble polymer, a water-insoluble polymer, a small
molecular weight water-insoluble excipient, and one or more pharmaceutically
acceptable coating additives in a suitable solvent; and
, , , , , ,.(d ). , ~ P P I YW~o~a N% o@posjtipo~h wp (c) over the capsule core of step (b) to form g_yy UELF-LL L.3 s3- - - - - -
6
the pulsatile-release dosage form.
A ninth aspect of the present invention provides a process for the preparation of a pulsatilerelease
dosage form, wherein the process comprises the steps of:
(a) blendinglgranulating a drug, one or more gastro-retentive polymers, and one or more
pharmaceutically acceptable excipients;
(b) filling the blendslgranules of step (a) into a suitable sized capsule to form a capsule
core;
(c) dissolving/dispersing a water-soluble polymer, a water-insoluble polymer, a small
molecular weight water-insoluble excipient, and one or more pharmaceutically
acceptable coating additives in a suitable solvent; and
(d) applying the coating composition of step (c) over the capsule core of step (b) to form
the pulsatile-release dosage form.
The term "pulsatile-release dosage form", as used herein, refers to a dosage form designed
in such a way so that either some amount of the drug or the entire amount of the drug is released
after a predetermined period of time, i.e., lag time, upon administration of the dosage form.
The term "core", as used herein, refers to tablets, capsules, granules, caplets, spheroids, and
pellets, preferably tablets and capsules.
The coating layer delays the release of the drug from the core for a predetermined period of
time and irrespective of the pH of the medium to which it is exposed. It has been surprisingly
observed that incorporation of a small molecular weight water-insoluble excipient into the coating
blend of a water-soluble polymer and a water-insoluble polymer affords the desired lag time. The
small molecular weight water-insoluble excipient does not allow the water-insoluble polymer to
form a continuous film and the water-soluble polymer to form continuous pore channels. As a
result, when such a dosage form comes in contact with the fluids of the gastro-intestinal tract, the
water-soluble polymer gets solubilized. The channels formed by the water-soluble polymer are
however, not continuous, hence, drug release does not occur. Also, as the water-insoluble polymer
does not form a continuous film, the film strength is low and it disintegrates after a predetermined
lag time, after which some of or the entire amount of the drug gets released. Further, the release of
drug from said pulsatile-release dosage form is independent of the pH of the gastro-intestinal tract.
Further, when one or more rate-controlling polymers are incorporated in the core of said
pulsatile-release dosage form, some amount of dr1.1g will be released as a pulse aftei a
predetermined lag time and the remaining amount of the drug will be released continuously over a
.c* IPI. .T r. r n f 'I YY
.m m * - Lru. r i E L ~ iL Z - ~ Z - L ~ LPf ~- 4 5 7
prolonged period of time, thereby rendering extended-release benefits.
Alternatively, when one or more gastro-rctcntive polyillers are incorporated in the core of
said pulsatile-release dosage form, the dosage form would be retained in the upper gastro-intestinal
tract for a prolonged period of time. Subsequently, after a predetermined lag time, the drug is
released in the upper gastro-intestinal tract. Such a pulsatile-release dosage form is suitable for
drugs that are preferentially absorbed from the upper part of the gastro-intestinal tract.
The lag time provided by said pulsatile-release dosage form can be controlled by the
amount and type of water-soluble polymer, water-insoluble polymer, and small molecular weight
water-insoluble excipient employed in the coating layer, as well as the thickness of the coating
layer.
Examples of drugs which may be included in the pulsatile-release dosage form of the
present invention include, but are not limited to, anti-hypertensive drugs like losartan, olmesartan,
telmisartan, valsartan, clonidine, guanabenz, methyldopa, moxonidine, bumetanide, ethacrynic
acid, hrosemide, torsemide, epitizide, hydrochlorothiazide, chlorothiazide, bendroflumethiazide,
indapamide, chlorthalidone, metolazone, amiloride, triamterene, spironolactone, atenolol,
metoprolol, nadolol, nebivolol, oxprenolol, pindolol, propranolol, timolol, doxazosin,
phentolamine, indoramin, phenoxybenzamine, prazosin, terazosin, tolazoline, bucindolol,
carvedilol, labetalol, amlodipine, cilnidipine, felodipine, isradipine, lercanidipine, nicardipine,
nifedipine, nimodipine, nitrendipine, diltiazem, verapamil, captopril, enalapril, fosinopril, lisinopril,
perindopril, quinapril, ramipril, trandolapril, benazepril, candesartan, eprosartan, and irbesartan;
anti-inflammatory drugs like diclofenac, aspirin, celecoxib, diflunisal, etodolac, fenoprofen,
flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meloxicam, nabumetone, naproxen,
oxaprozin, piroxicam, salsalate, sulindac, and tolmetin; anti-hyperlipidemic drugs like simvastatin,
atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin,
and niacin; anti-asthmatic drugs like theophylline, tulobuterol, salbutamol, femoterol, terbutalin,
ipratropium bromide, oxitropium, aminophylline, beclomethasone, betamethasone, prednisolone,
sodium chromoglycate, nedocromil sodium, zafirleukast, and zileuton; glucocorticoids like
hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone,
betamethasone, triamcinolone, fludrocortisone acetate, and aldosterone; anti-ulcer drugs like
omeprazole, famotidine, ranitidine, cimetidine, pantoprazole, esomeprazole, lansoprazole, and
rabeprazole; anti-tumor drugs like oxaliplatin, fluorouracil, leucovorin, irinotecan, cisplastin,
doxorubicin, methotrexate, folinic acid, mercaptopurine, docetaxel, and paclitaxel; anti-Parkinson's
drugs like carbidopa, levodopa, and entacapone; or combinations thereof. The dose of any drug
Wl*9
may depend upon the individual drug us@ jn,tb pulsatile-release dosage form of the present
-c yo g B l b ~ ~ - 0 3 - 1 GI P~ -Ga8 4
invention.
Suitable water-soluble polymers are selected from the group consisting of hydroxypropyl
methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose,
polyethylene glycol, polyethylene oxide, polysaccharides, polyvinylpyrrolidone, polyvinyl alcohol,
and combinations thereof.
Suitable water-insoluble polymers are selected fiom the group consisting of cellulose ethers
such as ethyl cellulose; cellulose esters such as cellulose acetate; polyvinyl acetate; and
combinations thereof.
Suitable small molecular weight water-insoluble excipients are selected from the group
consisting of magnesium stearate, calcium stearate, cetyl alcohol, glyceryl behenate, talc, stearic
acid, glyceryl monostearate, hydrogenated vegetable oil, hydrogenated castor oil, magnesium
aluminum silicate, aluminum stearate, and combinations thereof.
The term "rate-controlling polymer", as used herein, refers to the agent that helps to control
the release of drug from the core. The rate-controlling polymer is selected from the group
consisting of cellulose derivatives such as hydroxypropyl methylcellulose available in various
grades (e.g., MethocelB K15 MCR and MethocelB E5), hydroxypropyl cellulose, carboxymethyl
cellulose, and ethyl cellulose; polysaccharides such as alginate, xanthan gum, carrageenan, and
starch; acrylic acid polymers like carbomer, polymethacrylate, poly(hydroxy ethyl methacrylate),
poly(methy1 methacrylate), and poly(hydroxy ethyl methacrylate-co methyl methacrylate);
polyethylene oxides and co-polymers thereof; polypropylene and co-polymers thereof; and
combinations thereof.
The term "gastro-retentive polymer", as used herein, refers to the agent that helps to retain
the dosage form in the stomach for a prolonged period of time. The gastro-retentive polymer is
selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymers
available under the trade names KollicoatB Protect and KollicoatB IR; acrylic acid polymers
available under the trade name CarbopolB; and combinations thereof.
The core of the present invention comprises one or more pharmaceutically acceptable
excipients that are routinely used in pharmaceutical dosage forms and are selected from the group
consisting of fillers, binders, disintegrants, lubricants/glidants, and combinations thereof.
Suitable fillers are selected fiom the group consisting of microcrystalline cellulose, silicified
microcrystalline cellulose, lactose, corn starch, glucose, calcium. carbonate, calcium phosphate
dibasic, calcium phosphate tribasic, calcium sulphate, starch, pregelatinized starch, lactitol,
Suitable binders are selected from the group consisting of methyl cellulose, ethyl cellulose,
hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl
cellulose sodium, acacia, guar gum, alginic acid, acrylic acid polymer, dextrin, maltodextrin,
magnesium aluminum silicate, polymethacrylates, polyvinylpyrrolidone, gelatin, starch, and
combinations thereof.
Suitable disintegrants are selected from the group consisting of hydroxypropyl cellulose,
microcrystalline cellulose, croscarmellose sodium, crospovidone, magnesium aluminum silicate,
methylcellulose, sodium alginate, sodium starch glycolate, starch, mannitol, alginic acid, and
combinations thereof.
Suitable lubricants/glidants are selected from the .group consisting of colloidal silicon
dioxide, stearic acid, magnesium stearate, zinc stearate, calcium stearate, talc, hydrogenated castor
oil, vegetable oil, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium
stearylfumarate, magnesium oxide, poloxamer, sodium lauryl sulphate, polyoxyethylene
monostearate, cocoa butter, mineral oil, polysaccharides, and combinations thereof.
The coating layer of the present invention comprises one or more pharmaceutically
acceptable coating additives routinely used in the pharmaceutical dosage forms selected from the
group consisting of plasticizers, opacifiers, anti-tacking agents, coloring agents, and combinations
thereof.
Suitable plasticizers are selected from the group consisting of triethyl citrate, dibutyl
sebacate, triacetin, acetylated triacetin, acetyl tributyl citrate, acetyl triethyl citrate, glycerin,
sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate,
diethyl malonate, dioctyl phthalate, tributyl citrate, glyceryl tributyrate, diacetylated
monoglyceride, rapeseed oil, olive oil, sesame oil, and combinations thereof.
Suitable opacifiers are selected from the group consisting of titanium dioxide, silicon
dioxide, manganese dioxide, iron oxide, and combinations thereof.
Suitable anti-tacking agents are selected from the group consisting of talc, magnesium
stearate, calcium stearate, stearic acid, silica, glyceryl monostearate, and combinations thereof.
Suitable coloring agents are selected from the group consisting of FD&C (Federal Food,
Drug and Cosmetic Act) approved coloring agents; natural coloring agents; natural juice
concentrates; pigments such as titanium dioxide, iron oxide, and zinc oxide; and combinations
thereof.
- . v - - . - - - - - . - .--- - - -
Examples of solvents used for granulation or coating include ethanol, water, methylene
chloride, isopropyl alcohol, acetone, methanol, or combinations thereof.
The core can be prepared by usual blending or granulating techniques and the resultant
blends/granules can be compressed into a tablet using a conventional tabletting process, or filled
into a capsule of a suitable size using any conventional process.
Coating may be performed by applying the coating composition as a solution, suspension,
or blend using any conventional coating technique known in the art such as spray coating in a
conventional coating pan, a fluidized bed processor, dip coating, or compression coating. The
percentage of the coating build-up may be varied depending upon the desired lag time.
The following examples represent various embodiments according to the present invention.
The examples are given solely for the purpose of illustration and are not to be construed as
limitations of the present invention, as many variations thereof are possible without departing from
the spirit and scope of the invention.
EXAMPLES
Examples 1 and 2
Procedure:
Core:
1. Losartan potassium, microcrystalline cellulose, lactose, hydroxypropyl methyl
cellulose, crospovidone, and colloidal silicon dioxide were sifted through a suitable mesh
and blended.
2. Magnesium stearate was mixed with the blend of step 1.
3. The resultant blend of step 2 was compressed into tablets using appropriate tooling.
Coating Laver:
4. Ethyl. cellulose, hydroxypropyl methyl cellulose/polyvinylpyrrolidone, and triethyl
citrateltriacetin were dissolved in an ethanol and purified water mixture.
5. Magnesium stearate, talc, and titanium dioxide were dispersed into the solution of step
9 -IpQ -u-rL' mL C 1- q~w3 - Q 3 - 2 8 1 6~ r 145
12-
4.
6. The tablets of step 3 were coated in a pan coating machine using the coating solution
of step 5 to form pulsatile-release dosage forms.
In- Vitro Studies:
The tablets prepared according to Example 1 and Example 2 were subjected to dissolution
studies in 900 mL of O.1N HCI, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer using a USP
type I1 apparatus with a paddle speed at 50 rpm. The results of the release studies are represented
in Tablt: 1 and Table 2 below.
Table 1: Percentage (%) of In-Vitro Drug Release in USP Type I1 Apparatus (Media: 900 mL
of 0.1N HCl, pH.4.5 acetate buffer, and pH 6.8 phosphate buffer at 50 rpm) From Tablets
Prepared According to Example 1
Table 2: Percentage (%) of In-Vitro Drug Release in USP Type I1 Apparatus (Media: 900 mL
of 0.1N HCI, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer at 50 rpm) From Tablets
Prepared According to Example 2
Time mours)
0.5
1 .o
1.5
2.5
3.0
3.5
4.0
5.0
Drug Dissolved (Percent wlw)
Time (Hours)
8
10
11
12
13
14
15
16
0.1N HCl
0.0
0.0
0.2
13.0
28.8
79.6
103.5
-
Drug Dissolved (Percent wlw)
pH 4.5 Acetate Buffer
0.0
0.0
11.7
16.5
32.0
67.5
80.1
102.9
0.1N HCl
0.0
0.0
2.5
18.0
34.4
52.0
70.7
101.4
pH 6.8 Phosphate Buffer
0.0
0.0
1.8
16.5
36.2
79.4
100.4
-
pH 4.5 Acetate Buffer
0.0
0.0
13.9
36.2
56.4
72.0
80.1
103.5
pH 6.8 Phosphate Buffer
0.0
0.0
30.0
46.2
87.9
79.5
102.7
-
Examples 3-6
Procedure:
Ingredients
1. Losartan potassium, microcrystalline cellulose, lactose, hydroxypropyl methyl cellulose,
crospovidone, and colloidal silicon dioxide were sifted through a suitable mesh and
blended.
2. Magnesium stearate was mixed with the blend of step 1.
Quantity (mgltablet)
3. The resultant blend of step 2 was compressed into tablets using appropriate tooling.
Core
Coating Layer:
Exnmplc 3 Exarriyle 6
4. Ethyl cellulose, hydroxypropyl methyl cellulose and dibutyl sebacateltriethyl citrate were
dissolved in an ethanol and purified water mixture.
Losartan potassium
Microcrystalline cellulose
Lactose
Hydroxypropyl methyl
cellulose
Crospovidone
Colloidal silicon dioxide
Magnesium stearate
Core Weight
5. Magnesium stearate, talc, titanium dioxide, and iron oxide red (Examples 4, 5 and 6)
Example 4
100.00
50.00
42.00
42.00
60.00
3 .OO
3.00
300.00
. - -- -- ~ .. . .
-.
were dispersed into the soiution of step 4.
Exaiiiple 5
100.00
150.00
120.00
70.00
. . .
50.00
5.00
5.00
500.00
100.00
150.00
120.00
70.00
50.00
5.00
5.00
500.00
Coating Layer
100.00
150.00
120.00
70.00
50.00
5.00
5.00
500.00
24.00
12.00
- -
3.00
27.00
6.00
2.63
0.38
q.s.
q.s.
75.01
575.01
Ethylcellulose
Hydroxypropyl methyl
cellulose
Dibutyl sebacate
Triethyl citrate
Magnesium stearate
Talc
Titanium dioxide
Iron oxide red
Ethanol
Purified water
Coating Weight
Total Weight
12.63
3.16
0.95
-
9.47
2.37
1.42
-
q.s.
q.s.
30.00
330.00
8.00
4.00
-
1 .OO
9.00
2.00
0.88
0.12
q.s.
q.s.
25.00
525.00
16.00
8.00
-
2.00
18.00
4.00
1.75
0.25
q.s.
q.s.
50.00
550.00
6. The tablets of step 3 were coated in a pan coating machine using the coating solution of
step 5 to form pulsatile-release dosage forms.
Example 7
Procedure:
1. Diclofenac sodium, microcrystalline cellulose, lactose, hydroxyl propyl methyl
cellulose, crospovidone, and colloidal silicon dioxide were sifted through a suitable mesh
and blended.
2. Magnesium stearate was mixed with the blend of step 1.
3. The resultant blend of step 2 was compressed into tablets using appropriate tooling.
Coating Layer:
4. Ethyl cellulose, hydroxypropyl methyl cellulose, and dibutyl sebacate were dissolved
in an ethanol and purified water mixture.
5. Magnesium stearate, talc, and titanium dioxide were dispersed into the solution of step
6. The tablets of step 3 were coated in a pan coating machine using the coating solution
of step 5 to form pulsatile-release dosage forms.
Example 8 and Example 9
Procedure:
Ingredients
Quantity (mgttablet)
Example 8 - I Example 9
Core
Losartan potassium 100.00 100.00
Microcrystalline cellulose 50.00 50.00
~ e t h o c eKl 1~5 MCR 80.00 80.00
~ e t h o c eEl5~ 42.00 42.00
Lactose 22.00 22.00
Colloidal silicon dioxide 3 .OO 3.00
Magnesium stearate 3 .OO 3.00
Core Weight - 3flfl.110 300.00
Coating layer
1. Losartan potassium, microcrystalline cellulose, lactose, ~ e t h o c eIlS1~ 5 MCR,
~ e t h o c eEl5~, and colloidal silicon dioxide are sifted through a suitable mesh and blended.
Ethyl cellulose
Hydroxypropyl methyl cellulose
Dibutyl sebacate
Magnesium stearate
Talc
Titanium dioxide
Ethanol
Purified water
Coating Weight
Total Weight
2. Magnesium stearate is mixed with the blend of step .1.
3. The resultant blend of step 2 is compressed into tablets using appropriate tooling.
12.63
3.16
0.95
9.47
2.37
1.42
q.s.
q.s.
30.00
330.00
Coating Layer:
4. Ethyl cellulose, hydroxypropyl methyl cellulose, and dibutyl sebacate are dissolved in
an ethanol and purified water mixture.
18.95
4.74
1.43
14.20
3.55
2.13
q.s.
q.s.
45.00
345.00
5. Magnesium stearate, talc, and titanium dioxide are dispersed into the solution of step
4.
6. The tablets of step 3 are coated in a pan coating machine using the coating solution of
step 5 to form pulsatile-release dosage forms.
Examples 10 and 1 1
Procedure:
Core:
1. Diclofenac sodium, microcrystalline cellulose, lactose, ~ e t h o c eKl1~ S MCR, and
colloidal silicon dioxide are sifted through a suitable mesh and blended.
2. Magnesium stearate is mixed with the blend of step 1.
3. The resultant blend of step 2 is compressed into tablets using appropriate tooling.
Coating; Layer:
4. Ethyl cellulose, hydroxypropyl methyl cellulose, and dibutyl sebacate are dissolved in
an ethanol and purified water mixture.
5. Magnesium stearate, talc, and titanium dioxide are dispersed into the solution of step
4.
6. The tablets of step 3 are coated in a pan coating machine using the coating solution of
step 5 to form pulsatile-release dosage forms.
--- b l l a b A - ?.C.%C ,,, D ~ L E L~ ~ - U ~ - L Q17L 1Q45 17
Example 12
1. Losartan potassium, mannitol, ~ollicoat@Pro tect, CarbopolR, and colloidal silicon
dioxide are sifted through a suitable mesh and blended.
Titanium dioxide
Iron oxide red
Ethanol
Purified water
Coating Weight
Total Weight
2. Magnesium stearate is mixed with the blend of step 1.
3.50
0.50 . -
q.s.
q.s.
100.00
1100.00
3. The resultant blend of step 2 is compressed into tablets using appropriate tooling.
Procedure:
Core:
Coating, Layer:
4. Ethyl cellulose, hydroxypropyl methyl cellulose, and triethyl citrate are dissolved in
an ethanol and purified water mixture.
5. Magnesium stearate, talc, titanium dioxide, and iron oxide red are dispersed into the
solution of step 4.
6. The tablets of step 3 are coated in a pan coating machine using the coating solution of
step 5 to form pulsatile-release dosage forms.
Example 13
Procedure:
Core:
1. Losartan potassium, mannitol, and colloidal silicon dioxide are sifted through a suitable
mesh and blended.
2. A suitable sized capsule is filled with the blend of step 1.
3. The resultant capsule is band-sealed with a gelatin solution.
Coating Layer:
4. Ethyl cellulose, hydroxypropyl methyl cellulose, and triethyl citrate are dissolved in
an ethanol and purified water mixture.
5. Magnesium stearate, talc, titanium dioxide, and iron oxide red are dispersed into the
solution of step 4.
6. The capsules of step 3 are coated in a pan coating machine using the coating solution
of step 5 to form pulsatile-release dosage forms.

WE CLAIM
1. A pulsatile-release dosagc form comprising:
(a) a core comprising a drug and one or more pharmaceutically acceptable
excipients; and
(b) a coating layer over said core comprising a water-soluble polymer, a waterinsoluble
polymer, a small molecular weight water-insoluble excipient, and
one or more pharmaceutically acceptable coating additives.
2. The pulsatile-release dosage form of claim 1, wherein the water-soluble polymer is
selected from the group consisting of hydroxypropyl methyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose,
polyethylene glycol, polyethylene oxide, polysaccharides, polyvinylpyrrolidone,
polyvinyl alcohol, and combinations thereof.
3. The pulsatile-release dosage form of claim 1, wherein the water-insoluble polymer
is selected from the group consisting of ethyl cellulose, cellulose acetate, polyvinyl
acetate, and combinations thereof
4. The pulsatile-release dosage form of claim 1, wherein the small molecular weight
water-insoluble excipient is selected from the group consisting of magnesium
stearate, calcium stearate, cetyl alcohol, glyceryl behenate, talc, stearic acid,
glyceryl monostearate, hydrogenated vegetable oil, hydrogenated castor oil,
magnesium aluminum silicate, aluminium stearate, and combinations thereof.
5. The pulsatile-release dosage form of claim 1, wherein the coating layer comprises
hydroxypropyl methyl cellulose, ethyl cellulose, magnesium stearate, and one or
more pharmaceutically acceptable coating additives.
6. The pulsatile-release dosage form of claim 1, wherein.the coating layer comprises
polyvinylpyrrolidone, ethyl cellulose, magnesium stearate, and one or more
- - - - - - - - - - - - -
pharmaceutically acceptable coating additives.
7. The pulsatile-release dosage form of claim 1, wherein the pharmaceutically
acceptable excipients are selected from the group consisting of fillers, binders,
disintegrants, lubricantslglidants, and combinations thereof.
8. The pulsatile-release dosage form of claim 1, wherein the pharmaceutically
acceptable coating additives are selected Erom the group consisting of plasticizers,
opacifiers, anti-tacking agents, coloring agents, and combinations thereof.
9. The pulsatile-release dosage form of claim I, wherein the core further comprises
one or more rate-controlling polymers selected from the group consisting of
cellulose derivatives, polysaccharides, acrylic acid polymers, polyethylene oxides
and co-polymers thereof, polypropylene and co-polymers thereof, and
combinations thereof.
10. The pulsatile-release dosage form of claim 1, wherein the core further comprises
one or more gastro-retentive polymers selected from the group consisting of
polyvinyl alcohol-polyethylene glycol graft copolymers, acrylic acid polymers, and
combinations thereof.
1 1. The pulsatile-release dosage form of claim 1, wherein the core is selected from the
group consisting of tablets, capsules, granules, caplets, spheroids, and pellets.
12. A process for the preparation of the pulsatile-release dosage form of claim 1,
wherein the core is a tablet and the process comprises the steps of:
(a) blendinglgranulating a drug, optionally one or more rate-controlling
polymers or one or more gastro-retentive polymers, and one or more
pharmaceutically acceptable excipients;
(b) compressing the blendslgranules of step (a) into a tablet core using
appropriate tooling;
(c) dissolving/dispersing a water-soluble polymer, a water-insoluble polymer, a
- ..- - small molecular weigh! wate_r-insoluble excipient, and on_e or more- - . -
pharmaceutically acceptable coating additives in a - suitable solvent; -e -r- . 2 DEL=%IE 3 - c 3 - I . i ? % 6 19:4 & '
(d) applying the coating composition of step (c) over the tablet core of step (b) to
form the pulsatile-release dosage forms.
13. A process for the preparation of the pulsatile-release dosage form of claim 1,
wherein the core is a capsule and the process comprises the steps of:
(a) blendinglgranulating a drug, optionally one or more rate-controlling
polymers or one or more gastro-retentive polymers, and one or more
pharmaceutically acceptable excipients;
(b) filling the blendslgranules of step (a) into a suitable sized capsule to form a
capsule core;
(c) dissolving/dispersing a water-soluble polymer, a water-insoluble polymer, a
small molecular weight water-insoluble excipient, and one or more
pharmaceutically acceptable coating additives in a suitable solvent;
(d) applying the coating composition of step (c) over the capsule core of step (b)
to form the pulsatile-release dosage form.