U.S. patent application number 12/060885 was filed with the patent office on 2008-07-31 for dosage form comprising therapeutic formulation.
This patent application is currently assigned to ALZA CORPORATION. Invention is credited to Liang-Chang Dong, Steven Espinal, Vincent Joseph Ferrari, Patrick S.L. Wong.
Application Number | 20080181944 12/060885 |
Document ID | / |
Family ID | 22274837 |
Filed Date | 2008-07-31 |
United States Patent
Application |
20080181944 |
Kind Code |
A1 |
Dong; Liang-Chang ; et
al. |
July 31, 2008 |
Dosage Form Comprising Therapeutic Formulation
Abstract
A dosage form is disclosed comprising a semipermeable walled
container that houses a capsule, which capsule comprises a drug
formulation, a piston, and an osmotic composition. The dosage form
delivers the drug formulation through a passageway at a controlled
rate over a sustained-release period of time up to 24 hours.
Inventors: |
Dong; Liang-Chang;
(Sunnyvale, CA) ; Wong; Patrick S.L.; (Burlingame,
CA) ; Ferrari; Vincent Joseph; (Foster City, CA)
; Espinal; Steven; (Mountain View, CA) |
Correspondence
Address: |
DEWIPAT INCORPORATED
P.O. BOX 1017
CYPRESS
TX
77410-1017
US
|
Assignee: |
ALZA CORPORATION
New Brunswick
NJ
|
Family ID: |
22274837 |
Appl. No.: |
12/060885 |
Filed: |
April 2, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10373529 |
Feb 24, 2003 |
|
|
|
12060885 |
|
|
|
|
09353519 |
Jul 14, 1999 |
6551613 |
|
|
10373529 |
|
|
|
|
60099401 |
Sep 8, 1998 |
|
|
|
Current U.S.
Class: |
424/457 ;
514/177; 514/263.38 |
Current CPC
Class: |
A61K 9/0004
20130101 |
Class at
Publication: |
424/457 ;
514/177; 514/263.38 |
International
Class: |
A61K 9/52 20060101
A61K009/52; A61K 31/57 20060101 A61K031/57; A61K 31/522 20060101
A61K031/522 |
Claims
1. A dosage form for oral administration of a drug comprising: a
capsule; a drug formulation disposed in the capsule, the drug
formulation comprising a dosage of the drug and a pharmaceutically
acceptable carrier, the pharmaceutically acceptable carrier
comprising a member selected from the group consisting of a
poly(alkylene oxide) of 50,000 to 300,000 weight average molecular
weight, an alkali of carboxyalkylcellulose of 7,500 to 25,000
weight average molecular weight, a copoly(ethylene oxide-propylene
oxide) of 4,000 to 25,000 weight average molecular weight, a
poly(carboxylated vinyl) polymer, a polysaccharide comprising
hydroxyl and carboxyl groups of 250,000 to 400,000 weight average
molecular weight, a cyclodextrine, a solid polymerized ethylene
glycol, a thixotropic gel, a solid poly(ethylene glycol) of 500 to
10,000 weight average molecular weight; an expandable composition
disposed in the capsule, the expandable composition comprising an
osmopolymer, an osmagent, and a member selected from the group
consisting of hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, and hydroxypropylbutylcellulose,
wherein the expandable composition increases in volume in the
presence of an aqueous fluid; a wall surrounding the capsule, the
wall comprising a composition that is permeable to passage of fluid
and substantially impermeable to passage of the drug; an exit in
the wall for releasing the drug formulation from the capsule at a
sustained release rate over an extended period of time; and a
movable piston positioned between the drug formulation and the
expandable composition, the movable piston being in contacting
relation with the drug formulation and the expandable
composition.
2. The dosage form of claim 1, wherein the expandable composition
comprises sodium carboxymethylcellulose, sodium chloride, and
hydroxypropylmethycellulose.
3. The dosage form of claim 2, wherein the drug formulation
comprises progesterone, polyoxyl 35 castor oil, and acetylated
monoglyceride.
4. The dosage form of claim 1, wherein the expandable composition
comprises polyethylene oxide, sodium chloride, and
hydroxypropylmethylcellulose.
5. The dosage form of claim 4, wherein the polyethylene oxide
possesses a molecular weight of 2,000,000, and the
hydroxypropylmethylcellulose possesses a molecular weight of
9,200.
6. The dosage form of claim 4, wherein the drug formulation
comprises acyclovir, polyoxyethylene 20 stearate, polyoxyl 35
castor oil, and polyoxyl 40 stearate.
7. The dosage form of claim 6, wherein the wall surrounding the
capsule comprises cellulose acetate and polyethylene glycol.
8. The dosage form of claim 1, wherein the wall surrounding the
capsule is made of an injection-moldable composition comprising a
thermoplastic polymer.
9. The dosage form of claim 1, wherein the drug comprises a member
selected from the group consisting of progestins and estrogens.
10. The dosage form of claim 1, wherein the drug formulation
further comprises a surfactant selected from the group consisting
of polyoxyethylenated castor oil comprising 9 moles to 52 moles of
ethylene oxide, polyoxyethylenated sorbitan monopalmitate
comprising 20 moles of ethylene oxide, polyoxyethylenated sorbitan
monostearate comprising 4 moles of ethylene oxide,
polyoxyethylenated sorbitan tristearate comprising 20 moles of
ethylene oxide, polyoxyethylenated lauryl ether, polyoxyethylenated
stearic acid comprising 30 moles to 40 moles of ethylene oxide,
polyoxyethylenated stearyl alcohol comprising 2 moles of ethylene
oxide, and polyoxyethylenated oleyl alcohol comprising 2 moles of
ethylene oxide.
11. The dosage form of claim 1, wherein the drug comprises a member
selected from the group consisting of peptide, protein, protein
anabolic hormone, growth promoting hormone, endocrine system
hormone, porcine growth promoting hormone, bovine growth promoting
hormone, equine growth promoting hormone, human growth hormone,
hormones derived from the pituitary gland, hormones derived from
the hypothalamus gland, recombinant DNA, somatropin, gonadotropic
releasing hormone, follicle stimulating hormone, luteinizing
hormone, LH-RH, insulin, cochicine, chorionic gonadotropin hormone,
oxytocin, vasopressing adrenocorticothropic hormone, prolactin,
cosyntropin, bypressin, thyroid stimulating hormone, secretin,
pancroezymin, enkephalin, and glucagon.
12. The dosage form of claim 1, wherein the extended period of time
is up to twenty-four hours.
13. A method for administering a drug to a recipient, comprising
the steps of: administering to the recipient a dosage form
comprising: a capsule; a drug formulation disposed in the capsule,
the drug formulation comprising a dosage of the drug and a
pharmaceutically acceptable carrier, the dry pharmaceutically
acceptable carrier comprising a member selected from the group
consisting of a poly(alkylene oxide) of 50,000 to 300,000 weight
average molecular weight, an alkali of carboxyalkylcellulose of
7,500 to 25,000 weight average molecular weight, a copoly(ethylene
oxide-propylene oxide) of 4,000 to 25,000 weight average molecular
weight, a poly(carboxylated vinyl) polymer, a polysaccharide
comprising hydroxyl and carboxyl groups of 250,000 to 400,000
weight average molecular weight, a cyclodextrine, a solid
polymerized ethylene glycol, a thixotropic gel, a solid
poly(ethylene glycol) of 500 to 10,000 weight average molecular
weight; an expandable composition disposed in the capsule, the
expandable composition comprising an osmopolymer, an osmagent, and
a member selected from the group consisting of
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, and hydroxypropylbutylcellulose,
wherein the expandable composition increases in volume in the
presence of an aqueous fluid; a wall surrounding the capsule, the
wall comprising a composition that is permeable to passage of fluid
and substantially impermeable to passage of the drug; an exit in
the wall for releasing the drug formulation from the capsule at a
sustained release rate over an extended period of time; and a
movable piston positioned between the drug formulation and the
expandable composition, the movable piston being in contacting
relation with the drug formulation and the expandable
composition;
14. The method of claim 13, wherein administering to the recipient
a dosage form comprises administering to the recipient the dosage
form wherein the expandable composition comprises sodium
carboxymethylcellulose, sodium chloride, and
hydroxypropylmethycellulose.
15. The method of claim 14, wherein administering to the recipient
a dosage form comprises administering to the recipient the dosage
form wherein the drug formulation comprising progesterone, polyoxyl
35 castor oil, and acetylated monoglyceride.
16. The method of claim 13, wherein administering to the recipient
a dosage form comprises administering to the recipient the dosage
form wherein the expandable composition comprises polyethylene
oxide, sodium chloride, and hydroxypropylmethylcellulose.
17. The method of claim 16, wherein administering to the recipient
a dosage form comprises administering to the recipient the dosage
form wherein the drug formulation comprises acyclovir,
polyoxyethylene 20 stearate, polyoxyl 35 castor oil, and polyoxyl
40 stearate.
18. The method of claim 17, wherein administering to the recipient
a dosage form comprises administering to the recipient the dosage
form wherein the drug formulation comprises acyclovir,
polyoxyethylene 20 stearate, polyoxyl 35 castor oil, and polyoxyl
40 stearate.
19. The method of claim 18, wherein administering to the recipient
a dosage form comprises administering to the recipient the dosage
form wherein the wall surrounding the capsule comprises cellulose
acetate and polyethylene glycol.
20. The method of claim 13, wherein administering to the recipient
a dosage form comprises administering to the recipient the dosage
form wherein the drug comprises a member selected from the group
consisting of progestins and estrogens.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/373529, filed Feb. 24, 2003, which is a continuation of U.S.
application Ser. No. 09/353519, filed Jul. 14, 1999, now U.S. Pat.
No. 6,551,613, which claims the benefit of U.S. Provisional
Application No. 60/099401, filed Sep. 8,1998, the disclosures of
all of which are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention pertains to both a useful dosage form
and to the process of manufacturing the dosage form. More
particularly, the invention relates to a dosage form comprising a
wall that surrounds an internal compartment comprising a
therapeutic formulation, a piston, a driving member, and a
passageway for delivering the therapeutic formulation from the
dosage form. The invention concerns also a process for
manufacturing the dosage form comprising the steps of uniting the
components of the dosage form into the manufactured dosage form.
The invention relates also to a method of using the dosage form for
dispensing the therapeutic formulation at a controlled rate over a
sustained-release period of time.
BACKGROUND OF THE INVENTION
[0003] In the fields of pharmacy and medicine, many drugs are
blended with a pharmaceutically acceptable carrier for
administering to a patient. For example, many drugs are
administered to a patient by dissolving the drug in an aqueous or
in a non-aqueous pharmaceutically acceptable carrier, by suspending
the drug in a pharmaceutically acceptable solvent, or by
incorporating the drug into one of two phases of an acceptable oil
and water system.
[0004] These pharmaceutical preparations are useful as they can be
formulated for different routes of administration, including oral
use, administering into body openings such as the vagina and anus,
or applied topically. Their dose can be adjusted, and they can be
administered to children and adults.
[0005] The preparation of these pharmaceutical preparations
involves considerations on the part of the pharmacist, including
the purpose of the drug, internal or external use, concentration of
the drug, the pharmaceutical carrier, and other characteristics
that lead to the final pharmaceutical preparation. However, there
are serious shortcomings associated with these pharmaceutical
preparations; mainly, the absence of a dosage form for
administering the pharmaceutical preparations at a controlled rate
over a sustained-release period for administering the drug for a
therapeutic benefit.
[0006] It will be appreciated by those versed in the drug
dispensing art in view of the above presentation, that if a dosage
form is made available for delivering pharmaceutical formulations
that overcomes tribulations of the prior art, such a dosage form
would have a practical value in the drug dispensing art. Likewise,
it will be scientifically self-evident to those versed in the drug
delivery art, that if a dosage form is made available that can
administer pharmaceutical formulations comprising the prescribed
dose at a sustained-release and controlled rate, such an unexpected
dosage form would have an immediate acceptance for positive therapy
in both human and veterinary medicine.
OBJECTS OF THE INVENTION
[0007] Accordingly, in view of the above presentation it is an
immediate object of the invention to provide a dosage form that can
deliver a pharmaceutical formulation and thereby overcome the
tribulations of the prior art.
[0008] Yet another object of the invention is to provide a dosage
form that can deliver a pharmaceutical formulation at a
sustained-release and controlled rate over an extended time.
[0009] Yet another object of this invention is to provide a dosage
form that can deliver an initially dry pharmaceutical formulations
that converts to a liquid pharmaceutical formulation in the dosage
form during the use of the dosage form in a liquid environment of
use.
[0010] Another object of the invention is to provide a dosage form
comprising an internal capsule which comprises a liquid formulation
containing a drug and a separate layer possessing expansion
properties.
[0011] Another object of the invention is to provide a dosage form
comprising a non-aqueous liquid formulation comprising an orally
administrable drug that can deliver a prescribed dose of drug to a
patient in need of therapy.
[0012] Another object of the invention is to provide a dosage form
comprising a liquid formulation containing a liquid soluble drug
that can be dispensed in a known dose for a therapeutic
benefit.
[0013] Another object of the invention is to provide a dosage form
comprising a capsule containing a non-aqueous liquid in which a
protein or proteinaceous drug is dissolved or dispersed for
sustained-release administration at a controlled rate over
time.
[0014] Another object of the invention is to provide a dosage form
comprising a capsule that contains an emulsion-drug composition
that can be delivered at a controlled rate over a delivery period
up to 30 hours.
[0015] Another object of the invention is to provide a dosage form
comprising a capsule that comprises an expandable layer, a piston,
and a liquid formulation.
[0016] Another object of the invention is to provide a dosage form
comprising a semipermeable composition coated capsule that
comprises a drug-emulsion composition.
[0017] Another object of the invention is to provide a process for
manufacturing a dosage form, which process comprises the steps of
adding to a capsule a composition containing a drug, placing a
layer that expands when contacted by an aqueous fluid, closing the
capsule, and coating the capsules with a semipermeable coat.
[0018] Another object of the invention is to provide a process for
manufacturing a dosage form comprising a capsule, which capsule
comprises an expandable layer, a piston, and a formulation
containing a liquid and a drug.
[0019] Other objects, features, aspects and advantages of this
invention will be more apparent to those having ordinary skill in
the drug delivery art from the accompanying specification taken in
conjunction with the drawings and the claims.
BRIEF DESCRIPTION OF DRAWINGS
[0020] In the drawing figures, which are not drawn to scale, but
are set forth to illustrate operative embodiments of the invention,
the drawing figures are as follows:
[0021] FIG. 1 is a closed, general view of a dosage form provided
by the invention.
[0022] FIG. 2 is an opened view of the dosage form of FIG. 1,
wherein in FIG. 2 the dosage form is seen holding and storing a two
piece capsule comprising a body section and a cap section for
containing a liquid drug formulation.
[0023] FIG. 3 is an opened view of the dosage form by FIG. 1,
wherein in FIG. 3 the dosage form is seen containing a capsule made
as a unit piece which capsule contains a liquid drug
formulation.
[0024] FIG. 4 is an opened view of the dosage form of FIG. 1
comprising a capsule comprising a body section and a cap section
comprising a drug formulation and an osmotic composition, with the
capsule surrounded by a semipermeable wall with an exit
passageway.
[0025] FIG. 5 depicts a flow diagram for manufacturing a dosage
form of the invention.
[0026] In the drawing figures and in the specification, like parts
in related figures are identified by like numbers. The terms
appearing earlier in the specification, and in the description of
the drawing figures, as well as embodiments thereof, are further
described in the disclosure.
DETAILED DESCRIPTION OF INVENTION
[0027] Turning now to the drawings in detail, which drawings are
examples of dosage forms provided by the invention, and which
examples are not to be considered as limiting, one example of a
dosage form is seen in FIG. 1. In FIG. 1, a dosage form 10, is seen
in closed view, comprising a body 11, a wall 12 and passageway 13.
Wall 12 surrounds and forms an internal space, not seen in FIG. 1.
Dosage form 10 has a lead end 9 with passageway 13 and a bottom end
8.
[0028] In drawing FIG. 2, dosage form 10 is seen comprising body
11, wall 12 that surrounds and forms space 14. Wall 12 comprises
orifice 13 that connects space 14 with the exterior environment of
dosage form 10. Internal space 14 holds and stores a capsule
comprising a body section 16 and a cap section 17. The body section
16 is a component receiving section that is filled with a drug 19
or section 16 is filled a composition comprising drug 19 and a
pharmaceutically acceptable carrier, 18. The pharmaceutical carrier
18 can be initially dry, or initially wet. A composition 21
comprising an expandable hydrophilic polymer is present in the open
end of body 16 and closed by sliding cap 17 over body section 16.
In the manufacture wherein body 16 comprises a dry drug 19
composition, a solution or a suspension is formed in the capsule by
fluid being imbibed from the environment into the capsule for
mixing with the drug in situ.
[0029] The capsule is composed of two sections fitted together by
slipping or telescoping the cap section over the body section. This
provides a closed capsule whose capsule wall surrounds and
encapsulates a useful dry drug or liquid drug formulation. The
capsule composed of two section defines a hard capsule. Hard
capsules are made by dipping stainless steel mold into a bath that
contains a solution of a capsule wall forming material to coat the
mold with the capsule wall-forming material. The closed and filled
capsule is coated next with a composition comprising a
semipermeable polymer. The semipermeable composition can be applied
to the capsule sections before, or applied after, the sections are
joined with the final capsule. In another manufacture, the hard
two-section capsule can be made with each section having, matched
locking rings near their opened end that permits joining and
locking the rings together near the overlapping cap and body after
filling the capsule. In this manufacture, a pair of matched locking
rings are formed into the cap and into the body sections, and these
rings provide the locking means for securely holding together the
capsule. The capsule can be manually filled with the formulation,
or the capsule can be machine filled with the formulation. In the
final manufacture, the hard capsule is capsulated with a
semipermeable wall on the capsule's exterior surface. The
semipermeable wall is permeable to the passage of fluid and
substantially impermeable to the passage of drug.
[0030] Dosage form 10, in capsule body 16 comprises in one
manufacture an initially dry drug formulation, or an initially
liquid formulation. The dry formulation comprises drug 19 and a
pharmaceutically acceptable carrier 18. The dry drug formulation,
when dosage form 10 is in operation in a fluid environment, imbibes
fluid into dosage form 10 and self-converts from a dry formulation
to a liquid drug formulation. The drug formulation comprises 100 ng
to 1500 mg of drugs, or 0.5 wt % to 65 wt % of a drug. Examples of
drugs include progestins and estrogens. The progestins are
represented by a member selected from the group consisting of
progesterone, norethindrone, levonorgestrel, norgestimate,
northindrone and 17-hydroxyprogesterone. The estrogenic steroids
are represented by a member selected from the group consisting of
estrogen, estradiol, estradiol valerate, estradiol benzoate,
ethinyl estradiol, estrone, estrone acetate, estriol, and estriol
triacetate. Representative of drug comprise also diphenedol,
meclizine, anisidonie, diphenadione, diphenadione, erythrityl
tetranitrate, dizoxin, reserpine, acetazolamide,
bendroflumethiazide, chlorpropamide, tolazamide, phenaglycodol,
allopurinol, aspirin, aluminum aspirin, metholrexate, acetyl
sulfisoxazole, enitabas, and erythromycin.
[0031] The dosage form of the invention also delivers
pharmacologically active peptides, proteins, proteins anabolic
hormones, growth promoting hormones, endocrine system hormones,
porcine growth promoting hormone, bovine growth promoting hormone,
equine growth promoting hormones, bovine growth promoting hormone,
human growth promoting hormone, hormones derived from the pituitary
and hypothalamus glands, recombinant DNA, somatropin, gonadotropic
releasing hormone, follicle stimulating hormone, luteinizing
hormone, LH-RH, insulin, colchicine, chorionic gonadotropin,
oxytocin, vasopressing adrenocorticothrophic hormone, prolactin,
cosyntropin, bypressin, thyroid stimulating hormone, secretin,
pancroezymin, enkephalin, glucagon, and like drugs. The drugs are
disclosed in U.S. Pat. No. 4,111,201 issued to Theeuwes, and in
U.S. Pat. No. 4,951,494 issued to Wong, Theeuwes, and
Eckenhoff.
[0032] The dry pharmaceutically acceptable carrier for
homogeneously blending with drug 19 to provide a dry drug
formulation 19 are represented by a poly(alkylene oxide) of 50,000
to 300,000 weight average molecular weight, an alkali
carboyalkylcellulose of 7,500 to 25,000 weight average molecular
weight, a copoly (ethylene oxide-propylene oxide) polymer of 4,000
to 25,000 weight average molecular weight, a polysaccharide
comprising hydroxyl and carboxyl groups possessing a 250,000 to
400,000 weight average molecular weight, a poly(carboxylated vinyl)
polymer, a cyclodextrine, solid polymerized ethylene glycols, a
thixotropic gel that flows as a liquid but sets on standing during
storage, and a solid poly(ethylene glycol) comprising a molecular
weight of 500 to 10,000. The poly(alkylene oxide) polymers are
available from the Union Carbide Corporation, Dansbury, Conn.; the
poly(ethylene glycols) are disclosed in Patty's Industrial Hygiene
and Toxicology, by Clayton et al., Vol. 2C, pages 3844-3852, and
3901-3907, (1982) published by Wiley-Interscience Co.;
alkalicarboxyalkylcellulose are commercially available from
Hercules Co., Lafayette, Calif.; and the carbovinyl polymer are
available from B.F. Goodrich Co., Cleveland, Ohio.
[0033] The dosage form 10 can comprise 0.5 wt % to 60 wt % of a
pharmaceutically acceptable liquid carrier. The pharmaceutically
acceptable liquid can comprise a single component or it can
comprise more than one component. The pharmaceutically acceptable
carrier can comprise a surfactant, that serves to reduce
aggregation, reduce interfacial tension between components, enhance
the free flow of components, and lessen the incidence of component
retention in the dosage form. The drug formulation of this
invention, in one embodiment comprises a surfactant that imparts
emulsification to the drug formulation. The surfactant can be a
member selected from the group consisting of polyoxyethylenated
castor oil comprising 9 moles of ethylene oxide, polyoxyethylenated
castor oil comprising 15 moles of ethylene oxide,
polyoxyethylenated castor oil comprising 20 moles of ethylene
oxide, polyoxyethylenated castor oil comprising 25 moles of
ethylene oxide, polyoxyethylenated castor oil comprising 40 moles
of ethylene oxide, polyoxyethylenated castor oil comprising 52
moles of ethylene oxide, polyoxyethylendated sorbitan monopalmitate
comprising 20 moles of ethylene oxide, polyoxyethylenated sorbitan
monostearate comprising 4 moles of ethylene oxide,
polyoxyethylenated sorbitan tristearate comprising 20 moles of
ethylene oxide, polkyoxyethylenated stearic and comprising 8 moles
of ethylene oxide, polyoxyethylene lauryl ether, polyoxyethylenated
stearic acid comprising 40 moles of ethylene oxide,
polyoxyethylenated stearic acid comprising 30 moles of ethylene
oxide, polyoxyethylenated stearyl alcohol comprising 2 moles of
ethylene oxide, and polyoxyethylenated oleyl alcohol comprising 2
moles of surfactant. The surfactants are available from Atlas
Chemical Industries, Wilmington, Del.; Drew Chemical Corp.,
Boonton, N.J.; and GAF Corp., New York, N.Y.
[0034] The drug formulation can comprise an oil phase, blended with
the drug and the surfactant. The oil phase comprises a
pharmaceutically acceptable oil that is non-polar in nature, or
non-polar after synthesis. The oil can be an edible liquid such as
a non-polar ester of an unsaturated fatty acid, or mixtures of such
esters can be utilized for this purpose. The oil can be vegetable,
mineral, animal, or marine in origin. Examples of non-toxic oils
comprise a member selected from the group consisting of peanut oil,
cottonseed oil, sesame oil, olive oil, corn oil, almond oil,
mineral oil, castor oil, coconut oil, palm oil, cocoa butter oil,
safflower oil, a mixture of moni- and di-gylcerides of 16 to 18
carbon atoms, unsaturated fatty acids, fractionated trigylcerides
derived from coconut oil, and fractionated liquid triglycerides
derived from short chain 10 to 15 carbon atom fatty acid,
acetylated monoglycerides, acetylated triglycerides, olein known
also as glycerol trioleate, palmitin known also as glycerol
tripalmitate, stearin known also as glycerol tristearate, lauric
acid hexylester, olein acid oleylester, glycolyzed ethoxylated,
glyceride of natural oils, branched fatty acids with 13 molecules
of ethylene oxide, olein acid decylester, and branched liquid fatty
acids.
[0035] The pharmaceutically acceptable liquid carrier also embraces
liquid prepolymers, emulsions of the single phase and two-phase
types such as oil-in-water and water-in-oil, emulsions of castor
oil in aqueous solution of pigskin gelatin, emulsion of gum arabic,
oils with emulsifiers such as mono- or di-gylcerides of a fatty
acid, and lecithin and a fatty acid ester. The concentration of
oil, or oil derivatives in the drug liquid formulation is 1 wt % to
50 wt %, with the wt % of all components in the drug liquid
formulation equal to 100 wt %. The oils are disclosed in
Pharmaceutical Sciences by Remington, 17th Ed., pg. 403-405 (1985)
published by Mack Publishing Co., in Encyclopedia of Chemistry, by
Van Nostrand Reinhold Co., 4th Ed., pg. 644 to 645 (1984) published
by Van Nostrand Co.; in U.S. Pat. No. 4,259,323 issued to Ranucci;
and in U.S. Pat. No. 3,905,360 issued to Zaffaroni.
[0036] Dosage form 10 in capsule body 16 comprises an expandable
composition 21 that expands in the presence of imbibed aqueous and
biological fluids. Body 16 comprising expandable composition 21 is
closed by cap 17, to provide a closed capsule in dosage form 10.
Composition 21 is an expandable push driving force that acts in
cooperation with dosage form 10 for delivering drug 19 from dosage
form 10. Composition 21 exhibits fluid imbibing and/or absorbing
properties. Composition 21 comprises a hydrophilic polymer that can
interact with water and aqueous biological fluids and then swell or
expand. The hydrophilic polymers are known also as osmopolymers,
osmogels and hydrogels, and they exhibit a concentration gradient
across wall 12, whereby they imbibe fluid into dosage form 10.
Representative of hydrophilic polymers are poly(alkylene oxide) of
1,000,000 to 10,000,000 weight-average molecular weight including
poly(ethylene oxide), and an alkali carboxymethylcellulose of
10,000 to 6,000,000 weight average molecular weight including
sodium carboxymethylcellulose. Composition 21 comprises 10 mg to
425 mg of osmopolymer. Composition 21 can comprise 1 mg to 50 mg of
a poly(cellulose) of a member selected from the group consisting of
hydroxyethylcellulose, hydroxyproylcellulose,
hydroxypropylmethylcellulose, and hydroxypropylbutylcellulose.
Composition 21 comprises 0.5 mg to 175 mg of an osmotically
effective solute, known also as osmotic solute and osmagent, that
imbibe fluid through wall 12 into dosage form 10. The osmotically
effective solutes are selected from the group consisting of a salt,
acid, amine, ester and carbohydrate. Representative osmagents are
selected from the group consisting of magnesium sulfate, magnesium
chloride, potassium sulfate, sodium sulfate, lithuim sulfate,
potassium acid phosphate, mannitol, urea, inositol, magnesium
succinate, tartaric acid, sodium chloride, potassium chloride, and
carbohydrates such as raffinose, sucrose, glucose, lactose, and
sorbitol. Composition 21 optionally comprises 0 wt % to 3.5 wt % of
a colorant, such as ferric oxide. The total weight of all
components in composition 21 is equal to 100 wt %.
[0037] Dosage form 10 comprises a wall 12 that surrounds the
internal capsule. Wall 12 comprises a composition permeable to the
passage of fluid, aqueous and biological fluid, present in
environment of use, in animal including a human, and wall 12 is
substantially impermeable to the passage of drug 19, and the
components of emulsion formulation 19. Wall 12 is nontoxic, and it
maintains its physical and chemical integrity during the drug
delivery device of dosage form 10. Representative of materials for
forming wall 12, include semipermeable polymers, semipermeable
homopolymers, semipermeable copolymer, and semipermeable
terpolymers. The polymers comprise polymers including cellulose
esters, cellulose ethers, and cellulose ester-esters. These
cellulosic polymers have a degree of substitution, D.S., on their
anhydroglucose unit from greater than 0 up to 3 inclusive. By
degree of substitution is meant the average number of hydroxyl
groups originally present on the anhydroglucose unit that are
replaced by a substituting group, or converted into another group.
The anhydroglucose unit can be partially or completely substitute
with groups such as acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy,
halogen, carboalkyl, alkylcarbamate, alkylcarbonate,
alkylsulfonate, alkylsulfamate, and semipermeable polymer forming
groups.
[0038] The semipermeable materials typically include a member
selected from the group consisting of cellulose acylate, cellulose
diacylate, cellulose triacetate, cellulose acetate, cellulose
diacetate, cellulose triacetate, mono-, di- and tri-cellulose
alkanylates, mono-, di-, and tri-alkenylates, mono-, di-, and
tri-aroylates, and the like. Examplary polymers including cellulose
acetate having a D.S. of 1.8 to 2.3 and an acetyl content of 32 to
39.9%; cellulose diacetate having a D.S. of 1 to 2 and an acetyl
content of 21 to 35%; cellulose triacetate having a D.S. of 2 to 3
and an acetyl content of 34 to 44.8%; and the like. More specific
cellulosic polymers include cellulose proprionate having a D.S. of
1.8 and a propionyl content of 38.5%; cellulose acetate propionate
having an acetyl content of 1.5 to 7% and an acetyl content of 39
to 42%; cellulose acetate propionate having an acetyl content of
2.5 to 3%, an average propionyl content of 39.2 to 45% and a
hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having
a D.S. of 1.8, an acetyl content of 13 to 15%, and a butyryl
content of 34 to 39%; cellulose acette butyrate having an acetyl
content of 2 to 29.5%, a butyryl content of 17 to 53%, and a
hydroxyl content of 0.5 to 4.7%; cellulose triacylates having a
D.S. of 2.9 to 3 such as cellulose trivalerate, cellulose
trilaurate, cellulose tripalmitate, cellulose trioctanoate, and
cellulose tripropionate; cellulose diesters having a D.S. of 2.2 to
2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose
dioctanoate, cellulose dicarpylate and the like; mixed cellulose
esters such as cellulose acetate valerate, celluloser acetate
succinate, cellulose propionate succinate, cellulose acetate
octanoate, cellulose valerate palmitate, cellulose acetate
heptonate, cellulose valerate palmitate, cellulose acetate
heptonate, and the like. Semipermeable polymers are known in U.S.
Pat. No. 4,077,407, and they can be made by procedures described in
Encyclopedia of Polymer Science and Technology, Vol. 3, pages 325
to 354, 1965, published by Interscience Publishers, Inc., New
York.
[0039] Additional semipermeable polymers include cellulose
acetaldehyde dimethyl acetate; cellulose acetate ethylcarbonate;
cellulose acetate methylcarbamate; cellulose dimethylaminoacetate;
semipermeable polyamides; semipermeable polyurethanes;
semipermeable sulfonated polystyrenes; cross-linked, selectively
semipermeable polymers formed by the coprecipitation of a polyanion
and a polycation as disclosed in U.S. Pat. Nos. 3,173,876;
3,276,586; 3,541,005; 3,541,006; and 3,546,142; semipermeable
polymers as disclosed by Loeb and Sourirajan in U.S. Pat. No.
3,133,132; semipermeable polystyrene derivatives; semipermeable
poly(sodium styrenesulfonate); semipermeable
poly(vinylbenzyltrimethyl)ammonium chloride; semipermeable polymers
exhibiting a fluid permeability of 10 to 10 (cc.mil/cm.hr.atm)
expressed as per atmosphere of hydrostatic or osmotic pressure
difference across a semipermeable wall. The polymers are known to
the art in U.S. Pat. Nos. 3,845,770; 3,916,899; and 4,160,020, and
in Handbook of Common Polymers, by Scott, J. R. and Ross, W. J.,
1971, published by CRC Press, Cleveland, Ohio.
[0040] Drawing FIG. 3 illustrates another dosage form 10 provided
by this invention. In FIG. 3, dosage form 10 comprises a body 11,
comprising wall 12 with a passageway 13. Wall 12 surrounds and
defines internal compartment 14 housing internal capsule 20.
Internal capsule 20 in its final manufacture comprises a one piece
capsule that distinguishes capsule 20 from the two piece capsule
presented above. Capsule 20 comprises a composition comprising drug
19 and pharmaceutically acceptable carrier 18 as presented above.
Capsule 20 comprises also composition 21, the expandable
composition presented above. Capsule 20 in drawing FIG. 3 comprises
a movable piston 22. The movable piston 22 moves or slides in
response to pressure generated inside capsule 20. The piston 22 is
positioned between and in contacting relation with the liquid
formulation and expandable composition 21. The piston 22 serves to
reduce diffusion and/or migration between the liquid drug
formulation and the expandable composition, thereby maintaining the
concentration of the liquid formulation, and the piston 22 also
prevents interaction between the liquid formulation and the
expandable composition, thereby maintaining the stability of the
liquid formulation.
[0041] Dosage form 10 in operation imbibes fluid through wall 12
causing composition 19 to expand and apply pressure against piston
22. This applied pressure moves piston 22 towards passageway 13,
whereby the liquid drug formulation is pushed through passageway
into the environment of use. Representative of materials for
manufacturing movable piston 22 comprise a member selected from the
group consisting of a wax, petroleum wax, an ester of a high
molecular weight fatty acid with a high molecular weight alcohol, a
piston formed of an olefin polymer, a condensation polymer, rubber,
organosilicon, high density polyethylene, high density
polypropylene, and piston forming materials impermeable to
fluid.
[0042] In FIG. 3, capsule 20 is surrounded and/or coated by
semipermeable wall 12 presented above. Capsule 20 in FIG. 3
comprises a sealed construction encapsulating the drug formulation,
the piston, and the expandable composition. The capsule is made by
various processes including the plate process, the rotary die
process, the reciprocating die process, and the continuous process.
The place process uses a set of molds. A warm sheet of a prepared
capsule lamina-forming material is laid over the lower mold and the
formulation poured on it. A second sheet of the lamina-forming
material is placed over the formulation followed by the top mold.
The mold set is placed under a press and a pressure applied, with
or without heat to form a unit, capsule. The capsules are washed
with a solvent for removing excess agent formulation from the
exterior of the capsule, and the air-dried capsule is encapsulated
with a semipermeable wall.
[0043] The rotary die process uses two continuous films of capsule
lamina-forming material that are brought into convergence between a
pair of revolving dies and an injector wedge. The process fills and
seals the capsule in dual and coincident operations. In this
process, the sheets of capsule lamina-forming material are fed over
guide rolls, and then down between the wedge injector and the die
rolls. The agent formulation to be capsuled flows by gravity into a
positive displacement pump. The pump meters the agent formulation
through the wedge injector and into the sheets between the die
rolls. The bottom of the wedge contains small orifices lined up
with the die pockets of the die rolls. The capsule is about
half-sealed when the pressure of pumped agent formulation forces
the sheets into the die pockets, wherein the capsules are
simultaneously filled, shaped, hermetically sealed and cut from the
sheets of lamina-forming materials. The sealing of the capsule is
achieved by mechanical pressure on the die rolls and by heating of
the sheets of lamina-forming materials by the wedge. After
manufacture, the agent formulation-filled capsules are dried in the
presence of forced air, and a semipermeable lamina capsuled
thereto, by processes described hereafter.
[0044] The reciprocating die process produces capsules by leading
two films of capsule lamina-forming material between a set of
vertical dies. The dies as they close, open, and close perform as a
continuous vertical plate forming row after row of pockets across
the film. The pockets are filled with agent formulation, and as the
pockets move through the dies, they are sealed, shaped and cut from
the moving film as capsules filled with agent formulation. A
semipermeable capsulating lamina is coated thereon to yield the
capsule. The continuous process is a manufacturing system that also
uses rotary dies with the added feature that the process can
successfully fill active agent in dry power form into a soft
capsule, in addition to encapsulating liquids. The filled, capsule
of the continuous process is encapsulated with a semipermeable
polymeric material to yield the capsule. Procedures for
manufacturing unit capsules are disclosed in U.S. Pat. No.
4,627,850 issued to inventors Deters, Theeuwes, Mullins, and
Eckenhoff.
[0045] Drawing FIG. 4 illustrates another dosage form 10 provided
by the invention. In drawing FIG. 4, dosage form 10 comprises lead
end 9, trailing end 8, capsule cap 17, drug 19 and carrier 18 in
capsule body 16, expandable composition 21 in capsule body 16
closed by capsule cap 17. The components comprising FIG. 4 were
presented above, and that presentation is incorporated herein.
[0046] In drawing FIG. 4, dosage form 10 comprises wall 12 made
from an injection-moldable composition by an injection-molding
techniques. Injection-moldable compositions provided for
injection-molding into wall 12 comprise a thermoplastic polymer, or
the compositions comprise a mixture of thermoplastic polymers and
optional injection-molding ingredients. The thermoplastic polymer
that can be used for the present purpose comprise polymers that
have a low softening point, for example, below 200.degree. C.,
preferably within the range of 40.degree. C. to 180.degree. C. The
polymers, are preferably synthetic resins, for example, linear
polycondensation resins, condensation polymerized resins, addition
polymerized resins, such as polyamides, resins obtained from
diepoxides and primary alkanolamines, resins of glycerine and
phthalic anhydrides, polymethane, polyvinyl resins, polymer resins
with end-positions free or esterified carboxyl or carboxamide
groups, for example with acrylic acid, acrylic amide, or acrylic
acid esters,, polycaprolactone, and its copolymers with dilactide,
diglycolide, valerolactone and decalactone, a resin composition
comprising polycaprolactone and polyalkylene oxide, and a resin
composition comprising polycaprolactone, a polyalkylene oxide such
as polyethylene oxide, poly(cellulose) such as
poly((hydroxypropylmethylcellulose),
poly(hydroxyethylmethylcellulose), poly(hydroxyethylcellulose), and
poly(hydroxypropylkcellulose). The membrane forming composition can
comprises optical membrane-forming ingredients such as polyethylene
glycol, talcum, polyvinylalcohol, lactose, or polyvinyl
pyrrolidone. The compositions for forming an injection-molding
polymer composition can comprise 100% thermoplastic polymer. The
composition in another embodiment comprises 10% to 99% of a
thermoplastic polymer and 1% to 70% of a different polymer with the
total equal to 100%. The invention provides also a thermoplastic
polymer composition comprising 1% to 98% of a first thermoplastic
polymer, 1% to 90% of a different, second polymer and 1% to 90% of
a different, third polymer with all polymers equal to 100%.
Representation composition comprises 20% to 90% of thermoplastic
polycaprolactone and 10% to 80% of poly(alkylene oxide); a
composition comprising 20% to 90% of poly(alkylene oxide); a
composition comprising 20% to 90% polycaprolactone and 10% to 60%
of poly(ethylene oxide) with the ingredients equal to 100%; a
composition comprising of 10% to 97% polycaprolactone, 10% to 97%
poly(alkylene oxide), and 1% to 97% of poly(ethylene glycol) with
all ingredients equal to 100%; a composition comprising 20% to 90%
polycaprolactone and 10% to 80% of polyethylene glycol 40 stearate
(Myrj 525) with all ingredients equal to 100%; and a composition
comprising 1% to 90% polycaprolactone, 1% to 90% poly(ethylene
oxide), 1% to 90% poly(hydroxypropylcellulose) and 1% to 90%
poly(ethylene glycol) with all ingredients equal to 100%. The
percent, expressed is weight percent, wt %.
[0047] In another embodiment of the invention, a composition for
injection-molding to provide a membrane is prepared by blending a
composition comprising a polycaprolactone 63 wt %, polyethylene
oxide 27 wt %, and polyethylene glycol 10 wt % in a conventional
mixing machine, such as a Moriyama .RTM. Mixer at 65.degree. C. to
95.degree. C., with the ingredients added to the mixer in the
following addition sequence, polycaprolactone, polyethylene oxide
and polyethylene glycol. All the ingredients were mixed for 135
minutes at a rotor speed of 10 to 20 rpm. Next, the blend is fed to
a Baker Perkins Kneader.RTM. extruder at a 80.degree. C. to
90.degree. C., at a pump speed of 10 rpm and a screw speed of 22
rpm, and then cooled to 10.degree. C. to 12.degree. C. to reach a
uniform temperature. Then, the cooled extruded composition is fed
to an Albe Pelletizer, converted into pellets at 250.degree. C. and
a length of 5 mm. The pellets next are fed into an
injection-molding machine, an Arburg Allrounder.RTM. at 200.degree.
F. to 350.degree. F. (93.degree. C. 177.degree. C.), heated to a
molten polymeric composition, and the liquid polymer composition
forced into a mold cavity at high pressure and speed until the
molded is filled and the composition comprising the polymers are
solidified into a preselected shape. The parameters for the
injection-molding consists of a band temperature through zone 1 to
zone 5 of the barrel of 195.degree. F. (91.degree. C.) to
375.degree. F. (191.degree. C.), an injection-molding pressure of
1818 bar, a speed of 55 cm.sup.3/s, and a mold temperature of
75.degree. C. The injection-molding compositions and
injection-molding procedures are disclosed in U.S. Pat. No.
5,614,578 issued to Dong, Wong, Pollock, and Ferrari.
[0048] The expression passageway as used herein denotes means and
methods suitable for releasing the useful, active drug emulsion
formulation from the dosage form. The expression includes passage
way, aperture, hole, bore, pore and the like through the
semipermeable walls. The orifice can be formed by mechanical
drilling, laser drilling, or by eroding an erodible element, such
as a gelatin plug, a pressed glucose plug, to yield the orifice,
when the dosage form is in the environment of use. In an
embodiment, the orifice in wall 12 is formed in the environment of
use in response to the hydrostatic pressure generated in dosage
form 10. In another embodiment, the dosage form 10 can be
manufactured with two or more orifices in spaced-class relation for
delivering drug 20 from dosage form 10. The orifice 13, can be
formed by mechanical rupturing of wall 12 during operation of
dosage form 10. A detailed description of orifices and the maximum
and minimum dimensions of an orifice are disclosed in U.S. Pat.
Nos. 3,845,770 and 3,916,899 both issued to inventors Theeuwes and
Higuchi.
EXAMPLES OF THE INVENTION
[0049] The following examples are illustrative of the present
invention, and the examples should not be considered as limiting
the scope of this invention in any way, as these examples and other
equivalents thereof will become apparent to those versed in the
drug dispensing art in the light of the present disclosure, and the
accompanying claims.
Example 1
[0050] A dosage form is manufactured for dispensing a beneficial
drug orally to the gastrointestinal tract as follows: first, a
composition comprising expandable properties is prepared by adding
58.7 wt % sodium carboxymethylcellulose is added to the bowl of a
fluid bed granulator. Next, 30 wt % of sodium chloride, 5.0 wt %
hydroxyproplymethylcellulose of 11,300 molecular weight and 1 wt %
red ferric oxide are added to the fluid bed granulator. In a
separate container, a granulating solution is prepared by
dissolving 5.0 wt % hydroxypropylcellulose of 40,000 molecular
weight in purified water. Then, the granulating solution is sprayed
onto the fluidized powders until all the solution is applied and
the powders are granular. Next, 0.25 wt % of magnesium stearate is
blended with the granular. The composition is compressed into a
tablet with a conventional tablet press, as follows: two hundred
and fifty mg of the composition are added to a 9/32 inch punch,
tamped and then compressed under a force of about 1 metric ton into
a expandable osmogel tablet.
[0051] Next, a drug formulation is prepared as follows: 50 wt % of
progesterone, 33.4 wt % of polyoxyl 35 castor oil available as
Cremophor El from BASF Corp., Mount Olive, N.J., and 16.5 wt % of
acetylated monoglyceride available as Myvacet available from
Eastman Corp., Kingsport, Tenn., are mixed homogeneously using a
standard homogenizer.
[0052] Then, a capsule comprising a gelatin wall, size 0, is
separated into two segments, its body and its cap. Then, 600 mg of
the drug formulation is filled into the body of the capsule
followed by an osmotic tablet inserted into an injection-molded
wall with the osmotic tablet facing the bottom of the
injection-molded walled housing. Finally, the walls are crimped at
about 68.degree. C. to provide an exit passageway of 155 mil (3.875
mm).
Example 2
[0053] The procedure of Example 1 is repeated in the example for
providing the dosage form except a piston is place in contact with
the drug formulation followed by the expandable osmogel tablet
prior to forming the exit passageway in the injection-molded
wall.
Example 3
[0054] The procedure of Example 1 is repeated in this example for
providing the dosage form except in this example a piston is placed
in contact with the drug formulation, followed by the expandable
osmogel tablet, with the body of the capsule capped by the cap of
the capsule prior to forming the exit passageway in the outer
injection-molded wall.
Example 4
[0055] The procedure of Example 1 is followed for providing the
dosage form, except in this example the drug formulation comprises
50 wt % progesterone, 37.5 wt % polyoxyl 35 castor oil, and 12.5 wt
% acetylated monoglyceride.
Example 5
[0056] The procedure of Example 1 is repeated in this example for
providing a dosage form wherein the drug formulation comprises 50
wt % progesterone, 25 wt % polyoxyl 35 castor oil and 25 wt %
acetylated monoglyceride.
Example 6
[0057] The procedure of Example 1 is repeated in this example,
except herein the drug formulation comprises 50 wt % progesterone
and 50 wt % polyoxyl 35 castor oil.
Example 7
[0058] The procedure of Example 2 is followed in this example for
providing the dosage form, except in this example the drug
formulation comprises the drug formulation and the expandable
osmogel tablet, the capsule body is closed with the capsule cap,
prior to being placed in the injection-molded wall provided with an
exit passageway.
Example 8
[0059] A dosage form is manufactured for dispensing a beneficial
drug to the gastrointestinal tract of a human as follows: first, an
expandable composition is prepared in a fluid bed granulator. The
expandable composition comprises 30 wt % sodium chloride screened
through a 20 mesh screen added to the granulator bowl, followed by
58.75 wt % polyethylene oxide of 2,000,000 molecular weight. Then,
5 wt % hydroxypropylmethylcellulose possessing a 9,200 molecular
weight and 1 % red ferric oxide is added to the granulator bowl. In
a separate mixer, a granulation solution is prepared by dissolving
5 wt % hydroxypropylcellulose in purified water. Then, the
granulating solution is sprayed onto the fludized powders in the
granulator until all the solution is applied and the powders are
granular. Next 0.25 wt % magnesium stearate is blended with the
just prepared granules. The granules are compressed into a
tablet-shaped layer comprising 250 mg of granules in a 9/32 inch
punch, tamped, and then compressed under a force of 1 metric ton to
provide the osmogel driving tablet.
[0060] Next, a drug formulation is prepared as follows: first 50 wt
% of microfluidized acyclovir, 12.5 wt % polyoxyethylene 20
stearate, 25 wt % polyoxyl 35 castor oil available as Cremophor
El.RTM. from BASF Corp., Mount Olive, N.J., and 12.5 wt % polyoxyl
40 stearate commercially available as Myrj.RTM. 52 from ICI Inc.,
Wilmington, Del. are blended in a homogenizer to provide a
homogenous blend.
[0061] Next, a capsule made of pharmaceutically gelatin is
separated into its body and cap. The body is first charged with the
drug formulation, followed by a piston formed of high density
polyethylene, which is followed by the expandable composition. The
filled capsule body is closed with the gelatin cap.
[0062] Next, the assembled capsule is coated with a semipermeable
wall, which is applied from a wall forming composition. Then
wall-forming composition comprises 85 wt % cellulose acetate
comprising a 39.8% acetyl content, and 15 wt % polyethylene glycol
3350. The wall forming composition is dissolved in acetone/methanol
(80/20 wt/wt) cosolvent to make 4% solid solution. The solution is
sprayed onto the capsule in an air suspension coater. The
semipermeable wall coated capsules are dried in an oven at
50.degree. C. and 50.degree. relative humidity for 1 day to remove
all solvents. Then, a passageway is drilled in the semipermeable
wall to provide the drug dispensing dosage form. Accompanying FIG.
5 depicts a flow chart of a process for manufacturing the dosage
form of the invention.
METHOD OF USING THE DOSAGE FORM
[0063] The invention provides also a method of administering a drug
to a human patient. The method comprises orally admitting into the
gastrointestinal tract of a human the dosage form provide by the
invention. The method comprises the steps of (1) admitting orally
the dosage form into the gastrointestinal tract, which dosage form
comprises: (a) a wall for imbibing an external fluid,
aqueous-biological, through the wall into the dosage form, which
wall surrounds; (b) a capsule, the capsule comprising; (c) a drug
formulation, a piston and an osmotic driving force; and (d) an exit
in the semipermeable wall; (2) permitting imbibed aqueous fluid to
dissolve the gelatin capsule; (3) letting imbibed fluid mix with
the drug composition to form a dispensable composition; (4) letting
imbibed fluid be absorbed by the osmotic driving composition
thereby causing the composition swell, expand and push the drug
composition through the passageway at a controlled rate over a
sustained-release period up to twenty-four hours.
[0064] Inasmuch as the foregoing specification comprised
representative embodiments of the invention, it is understood that
changes, modifications and variations can be made herein, in
accordance with the inventive principles disclosed, without
departing from the scope of the invention.
* * * * *